PPARG Modulators for the Treatment of Osteoporosis

ABSTRACT

The invention provides methods of treatment of a progressive bone disease, such as osteoporosis, Paget&#39;s Disease, multiple myeloma, or hyperparathyroidism, comprising administration of an effective amount of a non-agonist PPARG modulator to a patient afflicted with the disease.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.17/168,690 (filed Feb. 5, 2021), which is a continuation of U.S. patentapplication Ser. No. 16/909,324 (filed Jun. 23, 2020; now abandoned),which is a continuation of U.S. patent application Ser. No. 16/028,730(filed Jul. 6, 2018; now U.S. Pat. No. 10,744,117), which is acontinuation of U.S. patent application Ser. No. 15/302,862 (filed Oct.7, 2016; now U.S. Pat. No. 10,016,394), which is a national stageapplication of International Application No. PCT/US2015/026226 (filedApr. 16, 2015; now expired), which claims the benefit of priority toU.S. Provisional Patent Application No. 61/980,444 (filed on Apr. 16,2014; now expired).

The disclosed subject matter herein is related to the subject matter ofU.S. Ser. No. 13/490,324 (now U.S. Pat. No. 8,957,093), Ser. No.13/811,965 (now U.S. Pat. No. 9,309,227), Ser. No. 13/490,342 (now U.S.Pat. No. 9,051,265), Ser. No. 13/811,969 (now abandoned), and Ser. No.13/811,973 (now abandoned).

The full disclosures of the aforementioned applications are incorporatedherein by reference in their entirety and for all purposes.

BACKGROUND

The peroxisome proliferator active receptors (PPARs), members of thenuclear hormone receptor superfamily, comprise several subtypes such asPPARα, PPARβ, and PPARγ. The PPARγ subtype, also referred to as PPARG,is the target of the glitazone pharmaceutical agents used for treatmentof type II diabetes. PPARG is also known as NR₁C₃ (the gene ID) andthere exist PPARG1 and PPARG2, the two major isoforms of PPARG. Theglitazones, such as pioglitazone and rosiglitazone, act as PPARGreceptor agonists. However, other classes of pharmaceutical agents, suchas Telmisartan, have been reported to act as partial agonists, bindingin a different mode to PPARG and having different cofactor requirements.See Y. Lamotte, et al., Bioorg. Med. Chem. Lett. (2010), 20, 1399-1404.

SUMMARY

The present invention is directed to methods of use of compounds thatare non-activating (non-agonist) PPARG modulators, compounds of formula(I) including compounds of formula (IA) and of formula (IB) as describedherein, in modulating the activity of PPARG, in treatment of conditionswherein non-activating modulation of PPARG is medically indicated, suchas for treatment of a progressive bone disease. Compounds of theinvention can block kinase-mediated, such as cdk5-mediated,phosphorylation of PPARG, but are not agonists of the receptor itself.By avoiding agonism of the receptor, it is believed that the compoundsmay exhibit no or reduced side effects associated with administration offull and partial agonists of PPARG, such as significant weight gain,edema, impairment of bone growth or formation, or cardiac hypertrophy,or any combination thereof, in the mammal receiving the compound. Forinstance, in practice of a method of treatment of a progressive bonedisease in a patient, such as treatment of osteoporosis, Paget'sDisease, multiple myeloma, hyperparathyroidism, and related progressivebone diseases, administration of an effective amount of a compound offormula (I) as disclosed herein can be used to treat the disease,wherein the effective dose of the compound acts to inhibit boneresorption, improve bone formation, or both, in the patient. Forexample, the method of treatment of the invention for the progressivebone disease can act to increase FGF21 while increasing bone health.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a schematic showing the differentiation of mesenchymal stemcells into osteoblasts and adipocytes under mediation of PPARG, alongwith bar graphs showing relative effects on PPARG target genes aP2 andALP induced by rosiglitazone, MRL24 (a Merck PPARG partial agonist) anda compound of formula (I), SR1664.

FIG. 2 is a bar graph showing the extent of bone formation marker inhuman mesenchymal stem cells upon treatment with a compound effectivefor practice of a method of the invention.

FIG. 3 schematically shows desirable molecular features of compounds forpracticing a method of the invention.

FIG. 4 provides bioactivity details for compounds effective for carryingout a method of the invention.

FIG. 5 indicates the results of a 4-week study of SR10171, a compoundeffective for carrying out a method of the invention, in comparison withrosiglitazone.

FIG. 6 shows bar graphs related to bone development, relative tocontrol, of SR10171, a compound effective for carrying out a method ofthe invention, in comparison with rosiglitazone.

FIG. 7 shows the results of a glucose tolerance test on mice fed aregular chow diet (RD) or obese mice fed a high fat diet (HFD). Micewere fasted overnight and then administered a bolus of glucose. Atseveral time intervals plasma glucose was measured. The data confirmsthe insulin sensitization effects and improved glucose disposal for TZDrosiglitazone treated mice. Similar results were obtained with SR10171demonstrating that this compound is an insulin sensitizer. Both drugtreated arms resulted in similar glucose disposal rates as the lean miceon RD.

FIG. 8 shows serum levels of FGF21, a liver-secreted hormone believed tohave beneficial effects in terms of metabolism, although over-expressionof FGF21 can be detrimental to bone. From Wei et al PNAS 2012 “Theendocrine hormone fibroblast growth factor 21 (FGF21) is a powerfulmodulator of glucose and lipid metabolism and a promising drug for type2 diabetes. Here we identify FGF21 as a potent regulator of skeletalhomeostasis. Both genetic and pharmacologic FGF21 gains of function leadto a striking decrease in bone mass. In contrast, FGF21 loss of functionleads to a reciprocal high-bone-mass phenotype. Mechanistically, FGF21inhibits osteoblastogenesis and stimulates adipogenesis from bone marrowmesenchymal stem cells by potentiating the activity of peroxisomeproliferator-activated receptor γ (PPAR-γ). Consequently, FGF21 deletionprevents the deleterious bone loss side effect of the PPAR-γ agonistrosiglitazone. Therefore, FGF21 is a critical rheostat for bone turnoverand a key integrator of bone and energy metabolism. These results revealthat skeletal fragility may be an undesirable consequence of chronicFGF21 administration.” Thus, while our compounds increase FGF21expression likely due to activation of PPARA, we inhibit the bad effectsby blocking PPARG.

FIG. 9 shows photographs depicting results of osmium staining in wholetibia and juxtaposed trabecular bone (gray) and fat (yellow) in proximaltibia. RD is regular diet (normal chow) and HFD is high fat diet (chowis 45% fat). Mice on HFD have increased fat accumulation in the bonemarrow as compared to lean controls. Mice on HFD and treated with a TZD,rosiglitazone, have significant fat accumulation in the bone marrow.Treatment of mice with SR10171 reduces the fat accumulation in bonemarrow to that below vehicle controls on high fat diet alone.

FIG. 10 shows quantitation of cortical bone mass from the midshaft tibiafrom mice treated under the conditions described above in FIG. 7 .Treatment of mice with SR10171 resulted in a statistically significantincrease in total tissue area, cortical bone area, and medular area.

FIG. 11 shows quantitative data on serum markers of bone resporption(TRACP5b) and bone formation (BALP) in mice treated under the conditionsdescribed in FIG. 7 . Treatment of mice on HFD with SR10171 reduced thelevel of TRACP5b to that of lean mice on normal chow diet. LikewiseSR10171 increase BALP significantly over the other treatment arms.

FIG. 12 shows pharmacokinetic properties of rosiglitazone and SR2595concentration in lean C57BL/6J mice treated for 21 days, two hoursfollowing drug administration (n=5) (a) plasma concentration (b)epididymal WAT concentration. Error bars are s.e.m.

FIG. 13 shows (A) mCT renderings and (B) measurements of trabecular bonein proximal tibia in lean C57BL/6 mice (BV/TV—bone mass; Tb.N—number oftrabeculae; Tb.Th—trabecular thickness; C=control; R=rosiglitazone;71=SR10171).

FIG. 14 shows dynamic histomorphometry of trabecular bone in proximaltibia double-labeled with calcein in lean C57BL/6 mice: (A)representative microphotographs of bone surface labeled with calcein,and (B) quantification of marrow apposition rate (MAR) and boneformation rate (BFR) (C=control; R=rosiglitazone; 71=SR10171).

FIG. 15 shows static histomorphometry of trabecular bone in proximaltibia in lean C57BL/6 mice (N.Ob—number of osteoblasts per boneperimeter; N.Oc—number of osteoclasts per bone perimeter; N.Ad—number ofadipocytes per region of interest; C=control; R=rosiglitazone;71=SR10171).

DETAILED DESCRIPTION Definitions

As used in the specification and the appended claims, the singular forms“a,” “an” and “the” include plural referents unless the context clearlydictates otherwise.

The term “about” as used herein, when referring to a numerical value orrange, allows for a degree of variability in the value or range, forexample, within 10%, or within 5% of a stated value or of a stated limitof a range.

All percent compositions are given as weight-percentages, unlessotherwise stated.

All average molecular weights of polymers are weight-average molecularweights, unless otherwise specified.

As used herein, “individual” (as in the subject of the treatment) or“patient” means both mammals and non-mammals. Mammals include, forexample, humans; non-human primates, e.g., apes and monkeys; andnon-primates, e.g., dogs, cats, cattle, horses, sheep, and goats.Non-mammals include, for example, fish and birds.

The term “disease” or “disorder” or “malcondition” are usedinterchangeably, and are used to refer to diseases or conditions whereinPPARG plays a role in the biochemical mechanisms involved in the diseaseor condition or symptom(s) thereof such that a therapeuticallybeneficial effect can be achieved by acting on PPARG. “Acting on” PPARG,or “modulating” PPARG, can include binding to PPARG and/or inhibitingthe bioactivity of PPARG and/or allosterically regulating thebioactivity of PPARG in vivo. When the term “modulator” is used herein,the term alludes to a compound of the invention, and it is understoodthat the terms “modulator” and “compound” or “compound of the invention”are synonymous when the context indicates that a compound of the presentinvention is being referred to.

In various embodiments, the compounds of the invention are not agonistsof PPARG, i.e., binding of the compound to PPARG does not activate thereceptor, as discussed in greater detail below. In various embodiments,compounds of the invention bring about inhibition of cdk5-mediatedphosphorylation of PPARG while being devoid of classical agonism. Suchcompounds are referred to herein as “non-agonist PPARG modulatorycompounds.”

The expression “effective amount”, when used to describe therapy to anindividual suffering from a disorder, refers to the amount of a compoundof the invention that is effective to inhibit or otherwise act on PPARGin the individual's tissues wherein PPARG involved in the disorder isactive, wherein such inhibition or other action occurs to an extentsufficient to produce a beneficial therapeutic effect.

“Substantially” as the term is used herein means completely or almostcompletely; for example, a composition that is “substantially free” of acomponent either has none of the component or contains such a traceamount that any relevant functional property of the composition isunaffected by the presence of the trace amount, or a compound is“substantially pure” is there are only negligible traces of impuritiespresent.

“Treating” or “treatment” within the meaning herein refers to analleviation of symptoms associated with a disorder or disease, orinhibition of further progression or worsening of those symptoms, orprevention or prophylaxis of the disease or disorder, or curing thedisease or disorder. Similarly, as used herein, an “effective amount” ora “therapeutically effective amount” of a compound of the inventionrefers to an amount of the compound that alleviates, in whole or inpart, symptoms associated with the disorder or condition, or halts orslows further progression or worsening of those symptoms, or prevents orprovides prophylaxis for the disorder or condition. In particular, a“therapeutically effective amount” refers to an amount effective, atdosages and for periods of time necessary, to achieve the desiredtherapeutic result.

A therapeutically effective amount is also one in which any toxic ordetrimental effects of compounds of the invention are outweighed by thetherapeutically beneficial effects. Phrases such as “under conditionssuitable to provide” or “under conditions sufficient to yield” or thelike, in the context of methods of synthesis, as used herein refers toreaction conditions, such as time, temperature, solvent, reactantconcentrations, and the like, that are within ordinary skill for anexperimenter to vary, that provide a useful quantity or yield of areaction product. It is not necessary that the desired reaction productbe the only reaction product or that the starting materials be entirelyconsumed, provided the desired reaction product can be isolated orotherwise further used.

By “chemically feasible” is meant a bonding arrangement or a compoundwhere the generally understood rules of organic structure are notviolated; for example a structure within a definition of a claim thatwould contain in certain situations a pentavalent carbon atom that wouldnot exist in nature would be understood to not be within the claim. Thestructures disclosed herein, in all of their embodiments are intended toinclude only “chemically feasible” structures, and any recitedstructures that are not chemically feasible, for example in a structureshown with variable atoms or groups, are not intended to be disclosed orclaimed herein.

An “analog” of a chemical structure, as the term is used herein, refersto a chemical structure that preserves substantial similarity with theparent structure, although it may not be readily derived syntheticallyfrom the parent structure. A related chemical structure that is readilyderived synthetically from a parent chemical structure is referred to asa “derivative.”

When a substituent is specified to be an atom or atoms of specifiedidentity, “or a bond”, a configuration is referred to when thesubstituent is “a bond” that the groups that are immediately adjacent tothe specified substituent are directly connected to each other in achemically feasible bonding configuration.

All chiral, diastereomeric, racemic forms of a structure are intended,unless a particular stereochemistry or isomeric form is specificallyindicated. Compounds used in the present invention can include enrichedor resolved optical isomers at any or all asymmetric atoms as areapparent from the depictions, at any degree of enrichment. Both racemicand diastereomeric mixtures, as well as the individual optical isomerscan be isolated or synthesized so as to be substantially free of theirenantiomeric or diastereomeric partners, and these are all within thescope of the invention.

As used herein, the terms “stable compound” and “stable structure” aremeant to indicate a compound that is sufficiently robust to surviveisolation to a useful degree of purity from a reaction mixture, andformulation into an efficacious therapeutic agent. Only stable compoundsare contemplated herein.

A “small molecule” refers to an organic compound, including anorganometallic compound, of a molecular weight less than about 2 kDa,that is not a polynucleotide, a polypeptide, a polysaccharide, or asynthetic polymer composed of a plurality of repeating units.

As to any of the groups described herein, which contain one or moresubstituents, it is understood that such groups do not contain anysubstitution or substitution patterns which are sterically impracticaland/or synthetically non-feasible. In addition, the compounds of thisdisclosed subject matter include all stereochemical isomers arising fromthe substitution of these compounds.

When a group, e.g., an “alkyl” group, is referred to without anylimitation on the number of atoms in the group, it is understood thatthe claim is definite and limited with respect the size of the alkylgroup, both by definition; i.e., the size (the number of carbon atoms)possessed by a group such as an alkyl group is a finite number, lessthan the total number of carbon atoms in the universe and bounded by theunderstanding of the person of ordinary skill as to the size of thegroup as being reasonable for a molecular entity; and by functionality,i.e., the size of the group such as the alkyl group is bounded by thefunctional properties the group bestows on a molecule containing thegroup such as solubility in aqueous or organic liquid media. Therefore,a claim reciting an “alkyl” or other chemical group or moiety isdefinite and bounded, as the number of atoms in the group cannot beinfinite.

The inclusion of an isotopic form of one or more atoms in a moleculethat is different from the naturally occurring isotopic distribution ofthe atom in nature is referred to as an “isotopically labeled form” ofthe molecule. All isotopic forms of atoms are included as options in thecomposition of any molecule, unless a specific isotopic form of an atomis indicated. For example, any hydrogen atom or set thereof in amolecule can be any of the isotopic forms of hydrogen, i.e., protium(¹H), deuterium (²H), or tritium (³H) in any combination. Similarly, anycarbon atom or set thereof in a molecule can be any of the isotopic formof carbons, such as ¹¹C, ¹²C, ¹³C, or ¹⁴C, or any nitrogen atom or setthereof in a molecule can be any of the isotopic forms of nitrogen, suchas ¹³N, ¹⁴N, or ¹⁵N. A molecule can include any combination of isotopicforms in the component atoms making up the molecule, the isotopic formof every atom forming the molecule being independently selected. In amulti-molecular sample of a compound, not every individual moleculenecessarily has the same isotopic composition. For example, a sample ofa compound can include molecules containing various different isotopiccompositions, such as in a tritium or ¹⁴C radiolabeled sample where onlysome fraction of the set of molecules making up the macroscopic samplecontains a radioactive atom. It is also understood that many elementsthat are not artificially isotopically enriched themselves are mixturesof naturally occurring isotopic forms, such as ¹⁴N and ¹⁵N, ³²S and ³⁴S,and so forth. A molecule as recited herein is defined as includingisotopic forms of all its constituent elements at each position in themolecule. As is well known in the art, isotopically labeled compoundscan be prepared by the usual methods of chemical synthesis, exceptsubstituting an isotopically labeled precursor molecule. The isotopes,radiolabeled or stable, can be obtained by any method known in the art,such as generation by neutron absorption of a precursor nuclide in anuclear reactor, by cyclotron reactions, or by isotopic separation suchas by mass spectrometry. The isotopic forms are incorporated intoprecursors as required for use in any particular synthetic route. Forexample, ¹⁴C and ³H can be prepared using neutrons generated in anuclear reactor. Following nuclear transformation, ¹⁴C and ³H areincorporated into precursor molecules, followed by further elaborationas needed.

In general, “substituted” refers to an organic group as defined hereinin which one or more bonds to a hydrogen atom contained therein arereplaced by one or more bonds to a non-hydrogen atom such as, but notlimited to, a halogen (i.e., F, Cl, Br, and I); an oxygen atom in groupssuch as hydroxyl groups, alkoxy groups, aryloxy groups, aralkyloxygroups, oxo(carbonyl) groups, carboxyl groups including carboxylicacids, carboxylates, and carboxylate esters; a sulfur atom in groupssuch as thiol groups, alkyl and aryl sulfide groups, sulfoxide groups,sulfone groups, sulfonyl groups, and sulfonamide groups; a nitrogen atomin groups such as amines, hydroxylamines, nitriles, nitro groups,N-oxides, hydrazides, azides, and enamines; and other heteroatoms invarious other groups. Non-limiting examples of substituents J that canbe bonded to a substituted carbon (or other) atom include F, Cl, Br, I,OR′, OC(O)N(R′)₂, CN, NO, NO₂, ONO₂, azido, CF₃, OCF₃, R′, O (oxo), S(thiono), methylenedioxy, ethylenedioxy, N(R′)₂, SR′, SOR′, SO₂R′,SO₂N(R′)₂, SO₃R′, C(O)R′, C(O)C(O)R′, C(O)CH₂C(O)R′, C(S)R′, C(O)OR′,OC(O)R′, C(O)N(R′)₂, OC(O)N(R′)₂, C(S)N(R′)₂, (CH₂)₀₋₂N(R′)C(O)R′,(CH₂)₀₋₂N(R′)N(R′)₂, N(R′)N(R′)C(O)R′, N(R′)N(R′)C(O)OR′,N(R′)N(R′)CON(R′)₂, N(R′)SO₂R′, N(R′)SO₂N(R′)₂, N(R′)C(O)OR′,N(R′)C(O)R′, N(R′)C(S)R′, N(R′)C(O)N(R′)₂, N(R′)C(S)N(R′)₂, N(COR′)COR′,N(OR′)R′, C(═NH)N(R′)₂, C(O)N(OR′)R′, or C(═NOR′)R′ wherein R′ can behydrogen or a carbon-based moiety, and wherein the carbon-based moietycan itself be further substituted; for example, wherein R′ can behydrogen, alkyl, acyl, cycloalkyl, aryl, aralkyl, heterocyclyl,heteroaryl, or heteroarylalkyl, wherein any alkyl, acyl, cycloalkyl,aryl, aralkyl, heterocyclyl, heteroaryl, or heteroarylalkyl or R′ can beindependently mono- or multi-substituted with J; or wherein two R′groups bonded to a nitrogen atom or to adjacent nitrogen atoms cantogether with the nitrogen atom or atoms form a heterocyclyl, which canbe mono- or independently multi-substituted with J.

When a substituent is monovalent, such as, for example, F or Cl, it isbonded to the atom it is substituting by a single bond. When asubstituent is more than monovalent, such as O, which is divalent, itcan be bonded to the atom it is substituting by more than one bond,i.e., a divalent substituent is bonded by a double bond; for example, aC substituted with O forms a carbonyl group, C═O, which can also bewritten as “CO”, “C(O)”, or “C(═O)”, wherein the C and the O are doublebonded. When a carbon atom is substituted with a double-bonded oxygen(═O) group, the oxygen substituent is termed an “oxo” group. When adivalent substituent such as NR is double-bonded to a carbon atom, theresulting C(═NR) group is termed an “imino” group.

When a divalent substituent such as S is double-bonded to a carbon atom,the results C(═S) group is termed a “thiocarbonyl” or “thiono” group.

Alternatively, a divalent substituent such as O or S can be connected bytwo single bonds to two different carbon atoms. For example, O, adivalent substituent, can be bonded to each of two adjacent carbon atomsto provide an epoxide group, or the O can form a bridging ether group,termed an “oxy” group, between adjacent or non-adjacent carbon atoms,for example bridging the 1,4-carbons of a cyclohexyl group to form a[2.2.1]-oxabicyclo system. Further, any substituent can be bonded to acarbon or other atom by a linker, such as (CH₂)_(n) or (CR′₂)_(n)wherein n is 1, 2, 3, or more, and each R′ is independently selected.

C(O) and S(O)₂ groups can also be bound to one or two heteroatoms, suchas nitrogen or oxygen, rather than to a carbon atom. For example, when aC(O) group is bound to one carbon and one nitrogen atom, the resultinggroup is called an “amide” or “carboxamide.” When a C(O) group is boundto two nitrogen atoms, the functional group is termed a “urea.” When aC(O) is bonded to one oxygen and one nitrogen atom, the resulting groupis termed a “carbamate” or “urethane.” When a S(O)₂ group is bound toone carbon and one nitrogen atom, the resulting unit is termed a“sulfonamide.” When a S(O)₂ group is bound to two nitrogen atoms, theresulting unit is termed a “sulfamate.”

Substituted alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl groupsas well as other substituted groups also include groups in which one ormore bonds to a hydrogen atom are replaced by one or more bonds,including double or triple bonds, to a carbon atom, or to a heteroatomsuch as, but not limited to, oxygen in carbonyl (oxo), carboxyl, ester,amide, imide, urethane, and urea groups; and nitrogen in imines,hydroxyimines, oximes, hydrazones, amidines, guanidines, and nitriles.

Substituted ring groups such as substituted cycloalkyl, aryl,heterocyclyl and heteroaryl groups also include rings and fused ringsystems in which a bond to a hydrogen atom is replaced with a bond to acarbon atom. Therefore, substituted cycloalkyl, aryl, heterocyclyl andheteroaryl groups can also be substituted with alkyl, alkenyl, andalkynyl groups as defined herein.

By a “ring system” as the term is used herein is meant a moietycomprising one, two, three or more rings, which can be substituted withnon-ring groups or with other ring systems, or both, which can be fullysaturated, partially unsaturated, fully unsaturated, or aromatic, andwhen the ring system includes more than a single ring, the rings can befused, bridging, or spirocyclic.

By “spirocyclic” is meant the class of structures wherein two rings arefused at a single tetrahedral carbon atom, as is well known in the art.

As to any of the groups described herein, which contain one or moresubstituents, it is understood, of course, that such groups do notcontain any substitution or substitution patterns which are stericallyimpractical and/or synthetically non-feasible. In addition, thecompounds of this disclosed subject matter include all stereochemicalisomers arising from the substitution of these compounds.

Alkyl groups include straight chain and branched alkyl groups andcycloalkyl groups having from 1 to about 20 carbon atoms, and typicallyfrom 1 to 12 carbons or, in some embodiments, from 1 to 8 carbon atoms.Examples of straight chain alkyl groups include those with from 1 to 8carbon atoms such as methyl, ethyl, n-propyl, n-butyl, n-pentyl,n-hexyl, n-heptyl, and n-octyl groups. Examples of branched alkyl groupsinclude, but are not limited to, isopropyl, iso-butyl, sec-butyl,t-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl groups. As usedherein, the term “alkyl” encompasses n-alkyl, isoalkyl, and anteisoalkylgroups as well as other branched chain forms of alkyl. Representativesubstituted alkyl groups can be substituted one or more times with anyof the groups listed above, for example, amino, hydroxy, cyano, carboxy,nitro, thio, alkoxy, and halogen groups.

Cycloalkyl groups are cyclic alkyl groups such as, but not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, andcyclooctyl groups. In some embodiments, the cycloalkyl group can have 3to about 8-12 ring members, whereas in other embodiments the number ofring carbon atoms range from 3 to 4, 5, 6, or 7. Cycloalkyl groupsfurther include polycyclic cycloalkyl groups such as, but not limitedto, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenylgroups, and fused rings such as, but not limited to, decalinyl, and thelike. Cycloalkyl groups also include rings that are substituted withstraight or branched chain alkyl groups as defined above. Representativesubstituted cycloalkyl groups can be mono-substituted or substitutedmore than once, such as, but not limited to, 2,2-, 2,3-, 2,4- 2,5- or2,6-disubstituted cyclohexyl groups or mono-, di- or tri-substitutednorbornyl or cycloheptyl groups, which can be substituted with, forexample, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, andhalogen groups. The term “cycloalkenyl” alone or in combination denotesa cyclic alkenyl group.

The terms “carbocyclic,” “carbocyclyl,” and “carbocycle” denote a ringstructure wherein the atoms of the ring are carbon, such as a cycloalkylgroup or an aryl group. In some embodiments, the carbocycle has 3 to 8ring members, whereas in other embodiments the number of ring carbonatoms is 4, 5, 6, or 7. Unless specifically indicated to the contrary,the carbocyclic ring can be substituted with as many as N−1 substituentswherein N is the size of the carbocyclic ring with, for example, alkyl,alkenyl, alkynyl, amino, aryl, hydroxy, cyano, carboxy, heteroaryl,heterocyclyl, nitro, thio, alkoxy, and halogen groups, or other groupsas are listed above. A carbocyclyl ring can be a cycloalkyl ring, acycloalkenyl ring, or an aryl ring. A carbocyclyl can be monocyclic orpolycyclic, and if polycyclic each ring can be independently be acycloalkyl ring, a cycloalkenyl ring, or an aryl ring.

(Cycloalkyl)alkyl groups, also denoted cycloalkylalkyl, are alkyl groupsas defined above in which a hydrogen or carbon bond of the alkyl groupis replaced with a bond to a cycloalkyl group as defined above.

Alkenyl groups include straight and branched chain and cyclic alkylgroups as defined above, except that at least one double bond existsbetween two carbon atoms. Thus, alkenyl groups have from 2 to about 20carbon atoms, and typically from 2 to 12 carbons or, in someembodiments, from 2 to 8 carbon atoms. Examples include, but are notlimited to vinyl, —CH═CH(CH₃), —CH═C(CH₃)₂, —C(CH₃)═CH₂,—C(CH₃)═CH(CH₃), —C(CH₂CH₃)═CH₂, cyclohexenyl, cyclopentenyl,cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl among others.

Cycloalkenyl groups include cycloalkyl groups having at least one doublebond between 2 carbons. Thus for example, cycloalkenyl groups includebut are not limited to cyclohexenyl, cyclopentenyl, and cyclohexadienylgroups. Cycloalkenyl groups can have from 3 to about 8-12 ring members,whereas in other embodiments the number of ring carbon atoms range from3 to 5, 6, or 7. Cycloalkyl groups further include polycyclic cycloalkylgroups such as, but not limited to, norbornyl, adamantyl, bornyl,camphenyl, isocamphenyl, and carenyl groups, and fused rings such as,but not limited to, decalinyl, and the like, provided they include atleast one double bond within a ring. Cycloalkenyl groups also includerings that are substituted with straight or branched chain alkyl groupsas defined above.

(Cycloalkenyl)alkyl groups are alkyl groups as defined above in which ahydrogen or carbon bond of the alkyl group is replaced with a bond to acycloalkenyl group as defined above.

Alkynyl groups include straight and branched chain alkyl groups, exceptthat at least one triple bond exists between two carbon atoms. Thus,alkynyl groups have from 2 to about 20 carbon atoms, and typically from2 to 12 carbons or, in some embodiments, from 2 to 8 carbon atoms.Examples include, but are not limited to —C≡CH, —C≡C(CH₃), —C≡C(CH₂CH₃),—CH₂C≡CH, —CH₂C≡C(CH₃), and —CH₂C≡C(CH₂CH₃) among others.

Aryl groups are cyclic aromatic hydrocarbons that do not containheteroatoms in the ring. Thus aryl groups include, but are not limitedto, phenyl, azulenyl, heptalenyl, biphenyl, indacenyl, fluorenyl,phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl,biphenylenyl, anthracenyl, and naphthyl groups. In some embodiments,aryl groups contain about 6 to about 14 carbons in the ring portions ofthe groups. Aryl groups can be unsubstituted or substituted, as definedabove. Representative substituted aryl groups can be mono-substituted orsubstituted more than once, such as, but not limited to, 2-, 3-, 4-, 5-,or 6-substituted phenyl or 2-8 substituted naphthyl groups, which can besubstituted with carbon or non-carbon groups such as those listed above.

Aralkyl or arylalkyl groups are alkyl groups as defined above in which ahydrogen or carbon bond of an alkyl group is replaced with a bond to anaryl group as defined above. Representative aralkyl groups includebenzyl and phenylethyl groups and fused (cycloalkylaryl)alkyl groupssuch as 4-ethyl-indanyl. Aralkenyl group are alkenyl groups as definedabove in which a hydrogen or carbon bond of an alkyl group is replacedwith a bond to an aryl group as defined above.

Heterocyclyl groups or the term “heterocyclyl” includes aromatic andnon-aromatic ring compounds containing 3 or more ring members, of which,one or more is a heteroatom such as, but not limited to, N, O, and S.Thus a heterocyclyl can be a cycloheteroalkyl, or a heteroaryl, or ifpolycyclic, any combination thereof. In some embodiments, heterocyclylgroups include 3 to about 20 ring members, whereas other such groupshave 3 to about 15 ring members. A heterocyclyl group designated as aC₂-heterocyclyl can be a 5-ring with two carbon atoms and threeheteroatoms, a 6-ring with two carbon atoms and four heteroatoms and soforth. Likewise a C₄-heterocyclyl can be a 5-ring with one heteroatom, a6-ring with two heteroatoms, and so forth. The number of carbon atomsplus the number of heteroatoms sums up to equal the total number of ringatoms. A heterocyclyl ring can also include one or more double bonds. Aheteroaryl ring is an embodiment of a heterocyclyl group. The phrase“heterocyclyl group” includes fused ring species including thosecomprising fused aromatic and non-aromatic groups. For example, adioxolanyl ring and a benzdioxolanyl ring system (methylenedioxyphenylring system) are both heterocyclyl groups within the meaning herein. Thephrase also includes polycyclic ring systems containing a heteroatomsuch as, but not limited to, quinuclidyl.

Heterocyclyl groups can be unsubstituted, or can be substituted asdiscussed above. Heterocyclyl groups include, but are not limited to,pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl,pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl,pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl,dihydrobenzofuranyl, indolyl, dihydroindolyl, azaindolyl, indazolyl,benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl,benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl,thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl,isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinylgroups. Representative substituted heterocyclyl groups can bemono-substituted or substituted more than once, such as, but not limitedto, piperidinyl or quinolinyl groups, which are 2-, 3-, 4-, 5-, or6-substituted, or disubstituted with groups such as those listed above.

Heteroaryl groups are aromatic ring compounds containing 5 or more ringmembers, of which, one or more is a heteroatom such as, but not limitedto, N, O, and S; for instance, heteroaryl rings can have 5 to about 8-12ring members. A heteroaryl group is a variety of a heterocyclyl groupthat possesses an aromatic electronic structure. A heteroaryl groupdesignated as a C₂-heteroaryl can be a 5-ring with two carbon atoms andthree heteroatoms, a 6-ring with two carbon atoms and four heteroatomsand so forth. Likewise a C₄-heteroaryl can be a 5-ring with oneheteroatom, a 6-ring with two heteroatoms, and so forth. The number ofcarbon atoms plus the number of heteroatoms sums up to equal the totalnumber of ring atoms. Heteroaryl groups include, but are not limited to,groups such as pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl,isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl,benzofuranyl, indolyl, azaindolyl, indazolyl, benzimidazolyl,azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl,imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl,xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl,tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. Heteroarylgroups can be unsubstituted, or can be substituted with groups as isdiscussed above. Representative substituted heteroaryl groups can besubstituted one or more times with groups such as those listed above.

Additional examples of aryl and heteroaryl groups include but are notlimited to phenyl, biphenyl, indenyl, naphthyl (1-naphthyl, 2-naphthyl),N-hydroxytetrazolyl, N-hydroxytriazolyl, N-hydroxyimidazolyl,anthracenyl (1-anthracenyl, 2-anthracenyl, 3-anthracenyl), thiophenyl(2-thienyl, 3-thienyl), furyl (2-furyl, 3-furyl), indolyl, oxadiazolyl,isoxazolyl, quinazolinyl, fluorenyl, xanthenyl, isoindanyl, benzhydryl,acridinyl, thiazolyl, pyrrolyl (2-pyrrolyl), pyrazolyl (3-pyrazolyl),imidazolyl (1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl),triazolyl (1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl 1,2,3-triazol-4-yl,1,2,4-triazol-3-yl), oxazolyl (2-oxazolyl, 4-oxazolyl, 5-oxazolyl),thiazolyl (2-thiazolyl, 4-thiazolyl, 5-thiazolyl), pyridyl (2-pyridyl,3-pyridyl, 4-pyridyl), pyrimidinyl (2-pyrimidinyl, 4-pyrimidinyl,5-pyrimidinyl, 6-pyrimidinyl), pyrazinyl, pyridazinyl (3-pyridazinyl,4-pyridazinyl, 5-pyridazinyl), quinolyl (2-quinolyl, 3-quinolyl,4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl), isoquinolyl(1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl,6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl), benzo[b]furanyl(2-benzo[b]furanyl, 3-benzo[b]furanyl, 4-benzo[b]furanyl,5-benzo[b]furanyl, 6-benzo[b]furanyl, 7-benzo[b]furanyl),2,3-dihydro-benzo[b]furanyl (2-(2,3-dihydro-benzo[b]furanyl),3-(2,3-dihydro-benzo[b]furanyl), 4-(2,3-dihydro-benzo[b]furanyl),5-(2,3-dihydro-benzo[b]furanyl), 6-(2,3-dihydro-benzo[b]furanyl),7-(2,3-dihydro-benzo[b]furanyl), benzo[b]thiophenyl(2-benzo[b]thiophenyl, 3-benzo[b]thiophenyl, 4-benzo[b]thiophenyl,5-benzo[b]thiophenyl, 6-benzo[b]thiophenyl, 7-benzo[b]thiophenyl),2,3-dihydro-benzo[b]thiophenyl, (2-(2,3-dihydro-benzo[b]thiophenyl),3-(2,3-dihydro-benzo[b]thiophenyl), 4-(2,3-dihydro-benzo[b]thiophenyl),5-(2,3-dihydro-benzo[b]thiophenyl), 6-(2,3-dihydro-benzo[b]thiophenyl),7-(2,3-dihydro-benzo[b]thiophenyl), indolyl (1-indolyl, 2-indolyl,3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl), indazole(1-indazolyl, 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl,7-indazolyl), benzimidazolyl (1-benzimidazolyl, 2-benzimidazolyl,4-benzimidazolyl, 5-benzimidazolyl, 6-benzimidazolyl, 7-benzimidazolyl,8-benzimidazolyl), benzoxazolyl (1-benzoxazolyl, 2-benzoxazolyl),benzothiazolyl (1-benzothiazolyl, 2-benzothiazolyl, 4-benzothiazolyl,5-benzothiazolyl, 6-benzothiazolyl, 7-benzothiazolyl), carbazolyl(1-carbazolyl, 2-carbazolyl, 3-carbazolyl, 4-carbazolyl),5H-dibenz[b,f]azepine (5H-dibenz[b,f]azepin-1-yl,5H-dibenz[b,f]azepine-2-yl, 5H-dibenz[b,f]azepine-3-yl,5H-dibenz[b,f]azepine-4-yl, 5H-dibenz[b,f]azepine-5-yl),10,11-dihydro-5H-dibenz[b,f]azepine(10,11-dihydro-5H-dibenz[b,f]azepine-1-yl,10,11-dihydro-5H-dibenz[b,f]azepine-2-yl,10,11-dihydro-5H-dibenz[b,f]azepine-3-yl,10,11-dihydro-5H-dibenz[b,f]azepine-4-yl,10,11-dihydro-5H-dibenz[b,f]azepine-5-yl), and the like.

Heterocyclylalkyl groups are alkyl groups as defined above in which ahydrogen or carbon bond of an alkyl group as defined above is replacedwith a bond to a heterocyclyl group as defined above. Representativeheterocyclyl alkyl groups include, but are not limited to, furan-2-ylmethyl, furan-3-yl methyl, pyridine-3-yl methyl, tetrahydrofuran-2-ylethyl, and indol-2-yl propyl.

Heteroarylalkyl groups are alkyl groups as defined above in which ahydrogen or carbon bond of an alkyl group is replaced with a bond to aheteroaryl group as defined above.

The term “alkoxy” refers to an oxygen atom connected to an alkyl group,including a cycloalkyl group, as are defined above. Examples of linearalkoxy groups include but are not limited to methoxy, ethoxy, propoxy,butoxy, pentyloxy, hexyloxy, and the like. Examples of branched alkoxyinclude but are not limited to isopropoxy, sec-butoxy, tert-butoxy,isopentyloxy, isohexyloxy, and the like. Examples of cyclic alkoxyinclude but are not limited to cyclopropyloxy, cyclobutyloxy,cyclopentyloxy, cyclohexyloxy, and the like. An alkoxy group can includeone to about 12-20 carbon atoms bonded to the oxygen atom, and canfurther include double or triple bonds, and can also includeheteroatoms. For example, an allyloxy group is an alkoxy group withinthe meaning herein. A methoxyethoxy group is also an alkoxy group withinthe meaning herein, as is a methylenedioxy group in a context where twoadjacent atoms of a structures are substituted therewith.

The terms “halo” or “halogen” or “halide” by themselves or as part ofanother substituent mean, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom, preferably, fluorine, chlorine, or bromine.

A “haloalkyl” group includes mono-halo alkyl groups, poly-halo alkylgroups wherein all halo atoms can be the same or different, and per-haloalkyl groups, wherein all hydrogen atoms are replaced by halogen atoms,such as fluoro. Examples of haloalkyl include trifluoromethyl,1,1-dichloroethyl, 1,2-dichloroethyl, 1,3-dibromo-3,3-difluoropropyl,perfluorobutyl, and the like.

A “haloalkoxy” group includes mono-halo alkoxy groups, poly-halo alkoxygroups wherein all halo atoms can be the same or different, and per-haloalkoxy groups, wherein all hydrogen atoms are replaced by halogen atoms,such as fluoro. Examples of haloalkoxy include trifluoromethoxy,1,1-dichloroethoxy, 1,2-dichloroethoxy, 1,3-dibromo-3,3-difluoropropoxy,perfluorobutoxy, and the like.

The terms “aryloxy” and “arylalkoxy” refer to, respectively, an arylgroup bonded to an oxygen atom and an aralkyl group bonded to the oxygenatom at the alkyl moiety. Examples include but are not limited tophenoxy, naphthyloxy, and benzyloxy.

An “acyl” group as the term is used herein refers to a group containinga carbonyl moiety wherein the group is bonded via the carbonyl carbonatom. The carbonyl carbon atom is also bonded to another carbon atom,which can be part of an alkyl, aryl, aralkyl cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl,heteroarylalkyl group or the like. In the special case wherein thecarbonyl carbon atom is bonded to a hydrogen, the group is a “formyl”group, an acyl group as the term is defined herein. An acyl group caninclude 0 to about 12-20 additional carbon atoms bonded to the carbonylgroup. An acyl group can include double or triple bonds within themeaning herein. An acryloyl group is an example of an acyl group. Anacyl group can also include heteroatoms within the meaning here. Anicotinoyl group (pyridyl-3-carbonyl) group is an example of an acylgroup within the meaning herein. Other examples include acetyl, benzoyl,phenylacetyl, pyridylacetyl, cinnamoyl, and acryloyl groups and thelike. When the group containing the carbon atom that is bonded to thecarbonyl carbon atom contains a halogen, the group is termed a“haloacyl” group. An example is a trifluoroacetyl group.

The term “amine” includes primary, secondary, and tertiary amineshaving, e.g., the formula N(group)₃ wherein each group can independentlybe H or non-H, such as alkyl, aryl, and the like. Amines include but arenot limited to R—NH₂, for example, alkylamines, arylamines,alkylarylamines; R₂NH wherein each R is independently selected, such asdialkylamines, diarylamines, aralkylamines, heterocyclylamines and thelike; and R₃N wherein each R is independently selected, such astrialkylamines, dialkylarylamines, alkyldiarylamines, triarylamines, andthe like. The term “amine” also includes ammonium ions as used herein.

An “amino” group is a substituent of the form —NH₂, —NHR, —NR₂, —NR₃ ⁺,wherein each R is independently selected, and protonated forms of each,except for —NR₃ ⁺, which cannot be protonated. Accordingly, any compoundsubstituted with an amino group can be viewed as an amine. An “aminogroup” within the meaning herein can be a primary, secondary, tertiaryor quaternary amino group. An “alkylamino” group includes amonoalkylamino, dialkylamino, and trialkylamino group.

An “ammonium” ion includes the unsubstituted ammonium ion NH₄ ⁺, butunless otherwise specified, it also includes any protonated orquaternarized forms of amines. Thus, trimethylammonium hydrochloride andtetramethylammonium chloride are both ammonium ions, and amines, withinthe meaning herein.

The term “amide” (or “amido”) includes C- and N-amide groups, i.e.,—C(O)NR₂, and —NRC(O)R groups, respectively. Amide groups thereforeinclude but are not limited to primary carboxamide groups (—C(O)NH₂) andformamide groups (—NHC(O)H). A “carboxamido” group is a group of theformula C(O)NR₂, wherein R can be H, alkyl, aryl, etc.

The term “urethane” (“carbamoyl” or “carbamyl”) includes N- andO-urethane groups, i.e., —NRC(O)OR and —OC(O)NR₂ groups, respectively.

The term “sulfonamide” (or “sulfonamido”) includes S- and N-sulfonamidegroups, i.e., —SO₂NR₂ and —NRSO₂R groups, respectively. Sulfonamidegroups therefore include but are not limited to sulfamoyl groups(—SO₂NH₂). An organosulfur structure represented by the formula—S(O)(NR)— is understood to refer to a sulfoximine, wherein both theoxygen and the nitrogen atoms are bonded to the sulfur atom, which isalso bonded to two carbon atoms.

The term “amidine” or “amidino” includes groups of the formula—C(NR)NR₂. Typically, an amidino group is —C(NH)NH₂.

The term “guanidine” or “guanidino” includes groups of the formula—NRC(NR)NR₂. Typically, a guanidino group is —NHC(NH)NH₂.

A “salt” as is well known in the art includes an organic compound suchas a carboxylic acid, a sulfonic acid, or an amine, in ionic form, incombination with a counterion. For example, acids in their anionic formcan form salts with cations such as metal cations, for example sodium,potassium, and the like; with ammonium salts such as NH₄ ⁺ or thecations of various amines, including tetraalkyl ammonium salts such astetramethylammonium, or other cations such as trimethylsulfonium, andthe like. A “pharmaceutically acceptable” or “pharmacologicallyacceptable” salt is a salt formed from an ion that has been approved forhuman consumption and is generally non-toxic, such as a chloride salt ora sodium salt. A “zwitterion” is an internal salt such as can be formedin a molecule that has at least two ionizable groups, one forming ananion and the other a cation, which serve to balance each other. Forexample, amino acids such as glycine can exist in a zwitterionic form. A“zwitterion” is a salt within the meaning herein. The compounds of thepresent invention may take the form of salts. The term “salts” embracesaddition salts of free acids or free bases which are compounds of theinvention. Salts can be “pharmaceutically-acceptable salts.” The term“pharmaceutically-acceptable salt” refers to salts which possesstoxicity profiles within a range that affords utility in pharmaceuticalapplications. Pharmaceutically unacceptable salts may nonethelesspossess properties such as high crystallinity, which have utility in thepractice of the present invention, such as for example utility inprocess of synthesis, purification or formulation of compounds of theinvention.

Suitable pharmaceutically-acceptable acid addition salts may be preparedfrom an inorganic acid or from an organic acid. Examples of inorganicacids include hydrochloric, hydrobromic, hydriodic, nitric, carbonic,sulfuric, and phosphoric acids. Appropriate organic acids may beselected from aliphatic, cycloaliphatic, aromatic, araliphatic,heterocyclic, carboxylic and sulfonic classes of organic acids, examplesof which include formic, acetic, propionic, succinic, glycolic,gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic,fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic,4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic),methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic,trifluoromethanesulfonic, 2-hydroxyethanesulfonic, p-toluenesulfonic,sulfanilic, cyclohexylaminosulfonic, stearic, alginic, β-hydroxybutyric,salicylic, galactaric and galacturonic acid. Examples ofpharmaceutically unacceptable acid addition salts include, for example,perchlorates and tetrafluoroborates.

Suitable pharmaceutically acceptable base addition salts of compounds ofthe invention include, for example, metallic salts including alkalimetal, alkaline earth metal and transition metal salts such as, forexample, calcium, magnesium, potassium, sodium and zinc salts.Pharmaceutically acceptable base addition salts also include organicsalts made from basic amines such as, for example,N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,ethylenediamine, meglumine (N-methylglucamine) and procaine. Examples ofpharmaceutically unacceptable base addition salts include lithium saltsand cyanate salts. Although pharmaceutically unacceptable salts are notgenerally useful as medicaments, such salts may be useful, for exampleas intermediates in the synthesis of Formula (I) compounds, for examplein their purification by recrystallization. All of these salts may beprepared by conventional means from the corresponding compound accordingto Formula (I) by reacting, for example, the appropriate acid or basewith the compound according to Formula (I). The term “pharmaceuticallyacceptable salts” refers to nontoxic inorganic or organic acid and/orbase addition salts, see, for example, Lit et al., Salt Selection forBasic Drugs (1986), Int J. Pharm., 33, 201-217, incorporated byreference herein.

A “hydrate” is a compound that exists in a composition with watermolecules. The composition can include water in stoichiometricquantities, such as a monohydrate or a dihydrate, or can include waterin random amounts. As the term is used herein a “hydrate” refers to asolid form, i.e., a compound in water solution, while it may behydrated, is not a hydrate as the term is used herein.

A “solvate” is a similar composition except that a solvent other thatwater replaces the water. For example, methanol or ethanol can form an“alcoholate”, which can again be stoichiometric or non-stoichiometric.As the term is used herein a “solvate” refers to a solid form, i.e., acompound in solution in a solvent, while it may be solvated, is not asolvate as the term is used herein.

In addition, where features or aspects of the invention are described interms of Markush groups, those skilled in the art will recognize thatthe invention is also thereby described in terms of any individualmember or subgroup of members of the Markush group. For example, if X isdescribed as selected from the group consisting of bromine, chlorine,and iodine, claims for X being bromine and claims for X being bromineand chlorine are fully described. Moreover, where features or aspects ofthe invention are described in terms of Markush groups, those skilled inthe art will recognize that the invention is also thereby described interms of any combination of individual members or subgroups of membersof Markush groups. Thus, for example, if X is described as selected fromthe group consisting of bromine, chlorine, and iodine, and Y isdescribed as selected from the group consisting of methyl, ethyl, andpropyl, claims for X being bromine and Y being methyl are fullydescribed.

If a value of a variable that is necessarily an integer, e.g., thenumber of carbon atoms in an alkyl group or the number of substituentson a ring, is described as a range, e.g., 0-4, what is meant is that thevalue can be any integer between 0 and 4 inclusive, i.e., 0, 1, 2, 3, or4.

In various embodiments, the compound or set of compounds, such as areused in the inventive methods, can be any one of any of the combinationsand/or sub-combinations of the above-listed embodiments.

In various embodiments, a compound as shown in any of the Examples, oramong the exemplary compounds, is provided. Provisos may apply to any ofthe disclosed categories or embodiments wherein any one or more of theother above disclosed embodiments or species may be excluded from suchcategories or embodiments.

The present invention further embraces isolated compounds of theinvention. The expression “isolated compound” refers to a preparation ofa compound of the invention, or a mixture of compounds the invention,wherein the isolated compound has been separated from the reagents used,and/or byproducts formed, in the synthesis of the compound or compounds.“Isolated” does not mean that the preparation is technically pure(homogeneous), but it is sufficiently pure to compound in a form inwhich it can be used therapeutically. Preferably an “isolated compound”refers to a preparation of a compound of the invention or a mixture ofcompounds of the invention, which contains the named compound or mixtureof compounds of the invention in an amount of at least 10 percent byweight of the total weight. Preferably the preparation contains thenamed compound or mixture of compounds in an amount of at least 50percent by weight of the total weight; more preferably at least 80percent by weight of the total weight; and most preferably at least 90percent, at least 95 percent or at least 98 percent by weight of thetotal weight of the preparation.

The compounds of the invention and intermediates may be isolated fromtheir reaction mixtures and purified by standard techniques such asfiltration, liquid-liquid extraction, solid phase extraction,distillation, recrystallization or chromatography, including flashcolumn chromatography, or HPLC.

Isomerism and Tautomerism in Compounds of the Invention Tautomerism

Within the present invention it is to be understood that a compound ofthe formula (I) or a salt thereof may exhibit the phenomenon oftautomerism whereby two chemical compounds that are capable of facileinterconversion by exchanging a hydrogen atom between two atoms, toeither of which it forms a covalent bond. Since the tautomeric compoundsexist in mobile equilibrium with each other they may be regarded asdifferent isomeric forms of the same compound. It is to be understoodthat the formulae drawings within this specification can represent onlyone of the possible tautomeric forms. However, it is also to beunderstood that the invention encompasses any tautomeric form, and isnot to be limited merely to any one tautomeric form utilized within theformulae drawings. The formulae drawings within this specification canrepresent only one of the possible tautomeric forms and it is to beunderstood that the specification encompasses all possible tautomericforms of the compounds drawn not just those forms which it has beenconvenient to show graphically herein. For example, tautomerism may beexhibited by a pyrazolyl group bonded as indicated by the wavy line.While both substituents would be termed a 4-pyrazolyl group, it isevident that a different nitrogen atom bears the hydrogen atom in eachstructure.

Such tautomerism can also occur with substituted pyrazoles such as3-methyl, 5-methyl, or 3,5-dimethylpyrazoles, and the like. Anotherexample of tautomerism is amido-imido (lactam-lactim when cyclic)tautomerism, such as is seen in heterocyclic compounds bearing a ringoxygen atom adjacent to a ring nitrogen atom. For example, theequilibrium:

is an example of tautomerism. Accordingly, a structure depicted hereinas one tautomer is intended to also include the other tautomer.

Optical Isomerism

It will be understood that when compounds of the present inventioncontain one or more chiral centers, the compounds may exist in, and maybe isolated as pure enantiomeric or diastereomeric forms or as racemicmixtures. The present invention therefore includes any possibleenantiomers, diastereomers, racemates or mixtures thereof of thecompounds of the invention.

The isomers resulting from the presence of a chiral center comprise apair of non-superimposable isomers that are called “enantiomers.” Singleenantiomers of a pure compound are optically active, i.e., they arecapable of rotating the plane of plane polarized light. Singleenantiomers are designated according to the Cahn-Ingold-Prelog system.The priority of substituents is ranked based on atomic weights, a higheratomic weight, as determined by the systematic procedure, having ahigher priority ranking. Once the priority ranking of the four groups isdetermined, the molecule is oriented so that the lowest ranking group ispointed away from the viewer. Then, if the descending rank order of theother groups proceeds clockwise, the molecule is designated as having an(R) absolute configuration, and if the descending rank of the othergroups proceeds counterclockwise, the molecule is designated as havingan (5) absolute configuration. In the example in the Scheme below, theCahn-Ingold-Prelog ranking is A>B>C>D. The lowest ranking atom, D isoriented away from the viewer. The solid wedge indicates that the atombonded thereby projects toward the viewer out of the plane of the paper,and a dashed wedge indicates that the atom bonded thereby projects awayfrom the viewer out of the plan of the paper, i.e., the plane “of thepaper” being defined by atoms A, C, and the chiral carbon atom for the(R) configuration shown below.

A carbon atom bearing the A-D atoms as shown above is known as a“chiral” carbon atom, and the position of such a carbon atom in amolecule is termed a “chiral center.” Compounds of the invention maycontain more than one chiral center, and the configuration at eachchiral center is described in the same fashion.

There are various conventions for depicting chiral structures usingsolid and dashed wedges. For example, for the (R) configuration shownabove, the following two depictions are equivalent:

The present invention is meant to encompass diastereomers as well astheir racemic and resolved, diastereomerically and enantiomerically pureforms and salts thereof. Diastereomeric pairs may be resolved by knownseparation techniques including normal and reverse phase chromatography,and crystallization.

“Isolated optical isomer” means a compound which has been substantiallypurified from the corresponding optical isomer(s) of the same formula.Preferably, the isolated isomer is at least about 80%, more preferablyat least 90% pure, even more preferably at least 98% pure, mostpreferably at least about 99% pure, by weight.

Isolated optical isomers may be purified from racemic mixtures bywell-known chiral separation techniques. According to one such method, aracemic mixture of a compound of the invention, or a chiral intermediatethereof, is separated into 99% wt. % pure optical isomers by HPLC usinga suitable chiral column, such as a member of the series of DAICEL®CHIRALPAK® family of columns (Daicel Chemical Industries, Ltd., Tokyo,Japan). The column is operated according to the manufacturer'sinstructions.

Description

The invention is directed, in various embodiments, to a method fortreatment of a patient afflicted by a progressive bone disease,comprising administering to the patient an effective dose of a compoundof formula (I)

wherein:

R is H, (C₁-C₆)alkyl, (C₃-C₉)cycloalkyl, or(C₃-C₉)cycloalkyl(C₁-C₆)alkyl;

Y¹ or Y² are each independently C or N, provided that when Y¹ or Y² isN, le or R², respectively, is absent;

R¹ and R² are independently H, (C₁-C₆)alkyl, (C₃-C₉)cycloalkyl, or(C₁-C₆)haloalkyl; or R¹ and R² together with the atoms to which they arebonded form a 5- to 9-membered ring, comprising 0-3 heteroatoms selectedfrom the group consisting of O, NR, and SO_(q) wherein q is 0, 1, or 2,and optionally mono- or multi-substituted with independently selected(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₆-C₁₀)aryl,(C₃-C₉)cycloalkyl, halo, oxo, (C₁-C₆)haloalkyl, nitro,cyano-(C₀-C₆)alkyl, R′O₂C—(C₀-C₆)alkyl, methylenedioxy,R′O—(C₀-C₆)alkyl, (R′)₂N—(C₀-C₆)alkyl, (R′)₂NC(═O)—(C₀-C₆)alkyl,R′C(═O)N(R′)—(C₀-C₆)alkyl, (C₁-C₆)alkyl-S(O)_(q)(C₀-C₆)alkyl, aryl,aroyl, or SO₂NR′₂;

R³ is optionally mono- or multi-substituted (C₁-C₆)alkyl,(C₁-C₆)alkenyl, (C₁-C₆)alkynyl, (C₆-C₁₀)aryl, (C₆-C₁₀)aryl(C₁-C₆)alkyl,(3-9 membered)heterocyclyl, (3-9 membered)heterocyclyl(C₁-C₆)alkyl, (3-9membered)heteroaryl, or (3-9 membered)heteroaryl(C₁-C₆)alkyl; wherein ifpresent each substituent on R³ is independently selected from the groupconsisting of (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,(C₆-C₁₀)aryl, (C₃-C₉)cycloalkyl, 3-9 membered mono- and bicyclicheterocyclyl, 3-9 membered mono- and bicyclic heteroaryl, halo, oxo,haloalkyl, haloalkoxy, nitro, cyano, CO₂R′, methylenedioxy, OR′, N(R′)₂,C(O)N(R′)₂, (C₁-C₆)alkyl-S(O)_(q), SO₂NR′₂, and (C₁-C₆)alkoxyl; andprovided that group R³N(R)C(═O)— can be bonded to any one of the fourcarbon atoms of the phenyl ring not bonded to N¹ or Y¹;

wherein each R′ is independently H, (C₁-C₆) alkyl, (C₃-C₉)cycloalkyl,(C₃-C₉)cycloalkyl(C₁-C₆)alkyl, (C₆-C₁₀)aryl, or (C₆-C₁₀)aryl(C₁-C₆)alkyl, or wherein two R′ bonded to an atom together with the atom form a3-9 membered ring optionally further comprising a heteroatom selectedfrom the group consisting of O, NR′, and S(O)_(q);

wherein any alkyl, alkenyl, alkynyl, aryl, arylalkyl, or cycloalkyl isoptionally mono- or independently multi-substituted with (C₁-C₆)alkyl,(C₁-C₆)haloalkyl, (C₁-C₆)alkoxy, (C₁-C₆)haloalkoxy, halo, oxo, aryl, oraroyl;

each of X¹-X⁵ is independently N or CH, or is C substituted with anindependently selected R⁴ or is C substituted with Z, provided that nomore than two of X¹-X⁵ are N, and provided that there is no more thanone Z group bonded to the ring comprising X¹—X⁵;

each R⁴ is independently halo, nitro, (C₁-C₆)fluoroalkyl,R′—(C₀-C₆)alkyl, R′O₂C—(C₀-C₆)alkyl, NC—(C₀-C₆)alkyl, R′O—(C₀-C₆)alkyl,(R′)₂N—(C₀-C₆)alkyl, (R′)₂NC(═O)—(C₀-C₆)alkyl,R′C(═O)N(R′)—(C₀-C₆)alkyl, C-bonded tetrazolyl,3-hydroxypyrrolidin-1-carbonyl, 2-hydroxyethylaminocarbonyl,cyclohexylaminocarbonyl,2-(N,N-dimethylaminocarbonyl)-2-hydroxyethylaminocarbonyl,N,N-dimethylaminoethylcarbonyl, N-methylaminocarbonyl,N-hydroxylaminocarbonyl, (1,3,4-oxadiazol-2(3H)-on)-yl,(1,2,4-oxadiazol-5(4H)-on)-3-yl, (C₁-C₆)alkyl-S(O)_(q)(C₀-C₆)alkyl,R'S(O)₂NHC(O), R′C(O)NHS(O)₂, an unsubstituted or substituted aryl, anunsubstituted or substituted heteroaryl, (C₁-C₆)alkyl or(C₃-C₉)cycloalkyl-(C₀-C₆)alkyl, wherein any alkyl or cycloalkyl isoptionally mono- or independently multi-substituted with R′, OR′,N(R′)₂, C-bonded tetrazolyl, (C₁-C₆)alkyl-S(O)_(q)(C₀-C₆)alkyl, anunsubstituted or substituted aryl, or an unsubstituted or substitutedheteroaryl; or R⁴ is —(C(R″)₂)_(m)CO₂R′, —(C(R″)₂)_(m)CON(R′)₂,—(C(R″)₂)_(m)CN, —O(C(R″)₂)_(m)CO₂R′, —O(C(R″)₂)_(m)CON(R′)₂, or—O(C(R″)₂)_(m)CN, wherein m is 1, 2, or 3;

R″ is H, halo, (C₁-C₆) alkyl, (C₁-C₆) haloalkyl, (C₃-C₉)cycloalkyl,(C₃-C₉)cycloalkyl(C₁-C₆)alkyl, (C₆-C₁₀)aryl, or (C₆-C₁₀)aryl(C₁-C₆)alkyl, or two R″ together with an atom to which they are bonded form a3- to 9-membered ring;

Z is a group of formula

wherein a wavy line indicates a point of bonding, each of Z¹-Z⁵ isindependently N or is C substituted with an independently selected H orR⁴; provided that no more than two of Z¹-Z⁵ are N;

Y is (C₁-C₂)alkyl, or sulfur;

when Y is (C₁-C₂)alkyl, R⁵ and R⁶ are independently H or (C₁-C₄)alkyl orindependently each R⁵ and R⁶ together with the carbon atom to which theyare bonded form a carbonyl, or, one R⁵ group can further be bonded to X⁵to form a 4- to 8-membered ring; and,

when Y is sulfur, R⁵ and R⁶ are both oxygen;

or a pharmaceutically acceptable salt thereof;

wherein the effective dose of the compound acts to inhibit boneresorption, improve bone formation, or both, in the patient.

For example, in various embodiments of practice of a method of theinvention, for a compound of formula (I), Y¹ or Y² can each be C,providing an indole nucleus. R¹ and R² can be independently H or methyl.In other embodiments, Y¹ is N and Y² is C, providing a benzimidazolenucleus, or Y¹ is C and Y² is N, providing an indazole nucleus for thecompound of formula (I) used in a method of the invention.

More specifically, R³ can be benzyl, α-phenethyl, α-phenpropyl,cycloalkyl or cycloalkylalkyl, any of which can be unsubstituted orsubstituted, as described herein. Or, R³ can be heterocyclyl,heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which can beunsubstituted or substituted. For instance, R³ can be any one of:

wherein a wavy line indicates a point of attachment.

In various embodiments for practice of a method of the invention, for acompound of formula (I), YR⁵R⁶ can be SO₂. In other embodiments, Y canbe C₁-alkyl; and R⁵ and R⁶ be H, or Y can be C₂-alkyl, and R⁵ and R⁶ beH.

Further embodiments for practice of a method of the invention comprisethe use of an effective dose of a compound of formula (I) wherein R⁴ is—CO₂H, —(CH₂)_(m)CO₂H, —O(CH₂)_(m)CO₂H, —CN, —(CH₂)_(m)CN,—O(CH₂)_(m)CN, —C(CH₃)₂CO₂H, —C(CH₃)₂CN, —OC(CH₃)₂CO₂H, —OC(CH₃)₂CN,—CH(CH₃)CO₂H, —CH(CH₃)CN, —OCH(CH₃)CO₂H, —OCH(CH₃)CN; —CH(CH₂CH₃)CO₂H,—CH(CH₂CH₃)CN, —OCH(CH₂CH₃)CO₂H, —OCH(CH₂CH₃)CN; —CH(i-Pr)CO₂H,—CH(i-Pr)CN, —OCH(i-Pr)CO₂H, —OCH(i-Pr)CN, wherein iPr indicatesisopropyl; —CH(t-Bu)CO₂H, —CH(t-Bu)CN, —OCH(t-Bu)CO₂H, —OCH(t-Bu)CN,wherein t-Bu indicates t-butyl; or —(CHR″)_(m)C(═O)N(R″)₂,—O(CHR″)_(m)C(═O)N(R″)₂,

wherein a wavy line indicates a point of attachment.

In various embodiments for practice of a method of the invention, forthe compound of formula (I), no Z group is present on the ringcomprising X¹—X⁵, providing a compound of formula (IA), which can be anN-benzyl-indole, an N-benzyl-benzimidazole, or an N-benzyl-indazole, oran analog thereof.

More specifically, for practice of a method of the invention, thecompound of formula (IA) can be any one of:

or a pharmaceutically acceptable salt thereof.

In other embodiments for practice of a method of the invention, for thecompound of formula (I), Z can be present, providing a compound offormula (IB). A compound of formula (IB) can be anN-biphenylmethyl-indole, an N-biphenylmethyl-benzimidazole, anN-biphenylmethyl-indazole, or an analog thereof. For instance, invarious embodiments, Z¹-Z⁵ can all be carbon. In other embodiments, oneof two of Z¹-Z⁵ can be nitrogen.

In specific embodiments for practice of a method of the invention, thecompound of formula (IB) can be any one of:

or a pharmaceutically acceptable salt thereof.

The invention provides, in various embodiments, methods of treatment ofa progressive bone disease, wherein the progressive bone disease isosteoporosis, Paget's Disease, multiple myeloma, or hyperparathyroidism.For instance, administration of the compound of formula (I) acts toincrease FGF21 while increasing bone health.

In various embodiments, the invention provides the use of a compound offormula (I) for treatment of a progressive bone disease, wherein thecompound of formula (I) is

wherein:

R is H, (C₁-C₆)alkyl, (C₃-C₉)cycloalkyl, or(C₃-C₉)cycloalkyl(C₁-C₆)alkyl;

Y¹ or Y² are each independently C or N, provided that when Y¹ or Y² isN, le or R², respectively, is absent;

R¹ and R² are independently H, (C₁-C₆)alkyl, (C₃-C₉)cycloalkyl, or(C₁-C₆)haloalkyl; or R¹ and R² together with the atoms to which they arebonded form a 5- to 9-membered ring, comprising 0-3 heteroatoms selectedfrom the group consisting of O, NR, and SO_(q) wherein q is 0, 1, or 2,and optionally mono- or multi-substituted with independently selected(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₆-C₁₀)aryl,(C₃-C₉)cycloalkyl, halo, oxo, (C₁-C₆)haloalkyl, nitro,cyano-(C₀-C₆)alkyl, R′O₂C—(C₀-C₆)alkyl, methylenedioxy,R′O—(C₀-C₆)alkyl, (R′)₂N—(C₀-C₆)alkyl, (R′)₂NC(═O)—(C₀-C₆)alkyl,R′C(═O)N(R′)—(C₀-C₆)alkyl, (C₁-C₆)alkyl-S(O)_(q)(C₀-C₆)alkyl, aryl,aroyl, or SO₂NR′₂;

R³ is optionally mono- or multi-substituted (C₁-C₆)alkyl,(C₁-C₆)alkenyl, (C₁-C₆)alkynyl, (C₆-C₁₀)aryl, (C₆-C₁₀)aryl(C₁-C₆)alkyl,(3-9 membered)heterocyclyl, (3-9 membered)heterocyclyl(C₁-C₆)alkyl, (3-9membered)heteroaryl, or (3-9 membered)heteroaryl(C₁-C₆)alkyl; wherein ifpresent each substituent on R³ is independently selected from the groupconsisting of (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,(C₆-C₁₀)aryl, (C₃-C₉)cycloalkyl, 3-9 membered mono- and bicyclicheterocyclyl, 3-9 membered mono- and bicyclic heteroaryl, halo, oxo,haloalkyl, haloalkoxy, nitro, cyano, CO₂R′, methylenedioxy, OR′, N(R′)₂,C(O)N(R′)₂, (C₁-C₆)alkyl-S(O)_(q), SO₂NR′₂, and (C₁-C₆)alkoxyl; andprovided that group R³N(R)C(═O)— can be bonded to any one of the fourcarbon atoms of the phenyl ring not bonded to N¹ or Y¹;

wherein each R′ is independently H, (C₁-C₆) alkyl, (C₃-C₉)cycloalkyl,(C₃-C₉)cycloalkyl(C₁-C₆)alkyl, (C₆-C₁₀)aryl, or (C₆-C₁₀)aryl(C₁-C₆)alkyl, or wherein two R′ bonded to an atom together with the atom form a3-9 membered ring optionally further comprising a heteroatom selectedfrom the group consisting of O, NR′, and S(O)_(q);

wherein any alkyl, alkenyl, alkynyl, aryl, arylalkyl, or cycloalkyl isoptionally mono- or independently multi-substituted with (C₁-C₆)alkyl,(C₁-C₆)haloalkyl, (C₁-C₆)alkoxy, (C₁-C₆)haloalkoxy, halo, oxo, aryl, oraroyl;

each of X¹-X⁵ is independently N or CH, or is C substituted with anindependently selected R⁴ or is C substituted with Z, provided that nomore than two of X¹-X⁵ are N, and provided that there is no more thanone Z group bonded to the ring comprising X¹—X⁵;

each R⁴ is independently halo, nitro, (C₁-C₆)fluoroalkyl,R′—(C₀-C₆)alkyl, R′O₂C—(C₀-C₆)alkyl, NC—(C₀-C₆)alkyl, R′O—(C₀-C₆)alkyl,(R′)₂N—(C₀-C₆)alkyl, (R′)₂NC(═O)—(C₀-C₆)alkyl,R′C(═O)N(R′)—(C₀-C₆)alkyl, C-bonded tetrazolyl,3-hydroxypyrrolidin-1-carbonyl, 2-hydroxyethylaminocarbonyl,cyclohexylaminocarbonyl,2-(N,N-dimethylaminocarbonyl)-2-hydroxyethylaminocarbonyl,N,N-dimethylaminoethylcarbonyl, N-methylaminocarbonyl,N-hydroxylaminocarbonyl, (1,3,4-oxadiazol-2(3H)-on)-yl,(1,2,4-oxadiazol-5(4H)-on)-3-yl, (C₁-C₆)alkyl-S(O)_(q)(C₀-C₆)alkyl,R'S(O)₂NHC(O), R′C(O)NHS(O)₂, an unsubstituted or substituted aryl, anunsubstituted or substituted heteroaryl, (C₁-C₆)alkyl or(C₃-C₉)cycloalkyl-(C₀-C₆)alkyl, wherein any alkyl or cycloalkyl isoptionally mono- or independently multi-substituted with R′, OR′,N(R′)₂, C-bonded tetrazolyl, (C₁-C₆)alkyl-S(O)_(q)(C₀-C₆)alkyl, anunsubstituted or substituted aryl, or an unsubstituted or substitutedheteroaryl; or R⁴ is —(C(R″)₂)_(m)CO₂R′, —(C(R″)₂)_(m)CON(R′)₂,—(C(R″)₂)_(m)CN, —O(C(R″)₂)_(m)CO₂R′, —O(C(R″)₂)_(m)CON(R′)₂, or—O(C(R″)₂)_(m)CN, wherein m is 1, 2, or 3;

R″ is H, halo, (C₁-C₆) alkyl, (C₁-C₆) haloalkyl, (C₃-C₉)cycloalkyl,(C₃-C₉)cycloalkyl(C₁-C₆)alkyl, (C₆-C₁₀)aryl, or (C₆-C₁₀)aryl(C₁-C₆)alkyl, or two R″ together with an atom to which they are bonded form a3- to 9-membered ring;

Z is a group of formula

wherein a wavy line indicates a point of bonding, each of Z¹-Z⁵ isindependently N or is C substituted with an independently selected H orR⁴; provided that no more than two of Z¹-Z⁵ are N;

Y is (C₁-C₂)alkyl, or sulfur;

when Y is (C₁-C₂)alkyl, R⁵ and R⁶ are independently H or (C₁-C₄)alkyl orindependently each R⁵ and R⁶ together with the carbon atom to which theyare bonded form a carbonyl, or, one R⁵ group can further be bonded to X⁵to form a 4- to 8-membered ring; and,

when Y is sulfur, R⁵ and R⁶ are both oxygen;

or a pharmaceutically acceptable salt thereof;

wherein the effective dose of the compound acts to inhibit boneresorption, improve bone formation, or both, in the patient.

For instance, the progressive bone disease can be osteoporosis, Paget'sDisease, multiple myeloma, or hyperparathyroidism. For instance,administration of the compound of formula (I) acts to increase FGF21while increasing bone health.

In various embodiments, the invention provides a compound of formula

or a pharmaceutically acceptable salt thereof.

The invention provides a method for practice of the invention whereinthe compound of formula (I) is

or a pharmaceutically acceptable salt thereof.

The invention provides a use of a compound of formula (I), wherein thecompound is

or a pharmaceutically acceptable salt thereof, for treatment of aprogressive bone disease, for instance, for treatment of osteoporosis,Paget's Disease, multiple myeloma, or hyperparathyroidism.

EXAMPLES Synthetic Methods

The following abbreviations are used throughout this document.

-   BOP Benzotriazol-1-yl-oxy-tris-(dimethylamino)phosphonium    hexafluorophosphate-   CDI Carbonyl diimidazole-   DBU Diazabicycloundecane-   DCM Dichloromethane-   DIPEA, ^(i)Pr₂EtN N,N-Diisopropylethylamine-   DMAP 4-(N,N-dimethylamino)pyridine-   DMF N,N-Dimethylformamide-   DMSO Dimethylsulfoxide-   EDAC 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride-   eq Equivalents-   Et₂O Diethyl ether-   EtOAc Ethyl acetate-   h Hours-   HATU O-(7-Azabenzotriazole-1-yl)-N, N,N′N′-tetramethyluronium    hexafluorophosphate-   HCl Hydrochloric acid-   HOAT Hydroxyazabenztriazole-   HOBT Hydroxybenzotriazole-   LiHDMS Lithium hexamethyldisilazide-   LiOH Lithium hydroxide-   mg Milligrams-   min Minutes-   mL Milliliters-   μL Microliters-   mmole Millimoles-   MS Mass spectroscopy-   MeOH Methanol-   NaBH₃CN Sodium cyanoborohydride-   NaH Sodium hydride-   NaIO₄ Sodium periodate-   NMM N-Methylmorpholine-   rb Round-bottom-   RT, rt Room temperature-   sat. Saturated-   TEA Triethylamine-   TFA Trifluoroacetic acid-   THF Tetrahydrofuran

SYNTHETIC EXAMPLES

Compounds of formula (IA)

Example 1:1-(2,4-Difluorobenzyl)-N-(2,4-dimethoxybenzyl)-1H-indole-5-carboxamide

Step 1: Methyl 1H-indole-5-carboxylate

To a solution of 1H-indole-5-carboxylic acid (1 g, 6.2 mmol, 1.0 equiv)in acetonitrile (40 mL) were added 1,8-Diazabicyclo[5.4.0]undec-7-ene(1.1 mL, 7.4 mmol, 1.2 equiv) and iodomethane (2.3 mL, 37.2 mmol, 6equiv). The solution was stirred under reflux overnight. The reactionmixture was concentrated in vacuo. The residue was dissolved in AcOEt,washed with a 0.5 N HCl aqueous solution, a saturated NaHCO₃ solutionand brine, dried over MgSO₄ and concentrated in vacuo. The obtained oilwas used in the next step without further purification.

Step 2: Methyl 1-(2,4-difluorobenzyl)-1H-indole-5-carboxylate

To a solution of methyl 1H-indole-5-carboxylate (2 g, 11.4 mmol, 1equiv) and 1-(bromomethyl)-2,4-difluorobenzene (1.61 mL, 12.6 mmol, 1.1equiv) in anhydrous DMF (50 mL) under argon atmosphere was added sodiumhydride (913 mg, 22.8 mmol, 2 equiv) in small portions. The mixture wasstirred 2 h at room temperature. The reaction mixture was thenneutralized by addition of methanol and concentrated in vacuo. Theresidue was dissolved in AcOEt, washed with brine and dried over MgSO₄.The crude was purified by flash chromatography (Hexane/AcOEt 7/3) toafford the title compound as a colorless oil (3.14 g, 10.4 mmol, 91%).ESI-MS (m/z): 302 [M+H]⁺.

Step 3: 1-(2,4-Difluorobenzyl)-1H-indole-5-carboxylic Acid

To a solution of methyl 1-(2,4-difluorobenzyl)-1H-indole-5-carboxylate(3.14 g, 10.4 mmol, 1 equiv) in methanol (50 mL) was added a 5 N NaOHsolution (50 mL, 104 mmol, 10 equiv). The reaction mixture was stirred 2h at 40° C. The mixture was then acidified and extracted with DCM. Afterconcentration in vacuo, the title compound was precipitated in Et₂O toafford a white powder (2.82 g, 9.8 mmol, 96%). ESI-MS (m/z): 288 [M+H]⁺.

Step 4:1-(2,4-Difluorobenzyl)-N-(2,4-dimethoxybenzyl)-1H-indole-5-carboxamide

To a solution of 1-(2,4-difluorobenzyl)-1H-indole-5-carboxylic acid (50mg, 0.17 mmol, 1 equiv) in DCM (2 mL) were added the(2,4-dimethoxyphenyl)methanamine (27 μL, 0.18 mmol, 1.05 equiv) and1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (35 mg, 0.18 mmol, 1.05equiv). The reaction mixture was stirred 2 h at room temperature. Thesolvent was removed in vacuo. The residue was dissolved in AcOEt andwashed with a 0.5 N HCl aqueous solution, a saturated NaHCO₃ solutionand brine, dried over MgSO₄ and concentrated in vacuo to afford a beigepowder (56 mg, 0.13 mmol, 76%). ESI-MS (m/z): 437 [M+H]⁺.

Example 2:1-(2,4-Difluorobenzyl)-N-(3-(trifluoromethoxy)benzyl)-1H-indole-5-carboxamide

The title compound was prepared following the same general protocol asdescribed in Step 4, Example 1, using(3-(trifluoromethoxy)phenyl)methanamine instead of the(2,4-dimethoxyphenyl)methanamine. A white powder was obtained (55 mg,0.12 mmol, 70%). ESI-MS (m/z): 461 [M+H]⁺.

Example 3:1-(2,4-Difluorobenzyl)-N-(3,4-dimethoxybenzyl)-1H-indole-5-carboxamide

The title compound was prepared following the same general protocol asdescribed in Step 4, Example 1, using (3,4-dimethoxyphenyl)methanamineinstead of the (2,4-dimethoxyphenyl)methanamine. A white powder wasobtained (44 mg, 0.10 mmol, 59%). ESI-MS (m/z): 437 [M+H]⁺.

Example 4:(S)-1-(2,4-Difluorobenzyl)-N-(1-(4-nitrophenyl)ethyl)-1H-indole-5-carboxamide

The title compound was prepared following the same general protocol asdescribed in Step 4, Example 1, using (S)-1-(4-nitrophenyl)ethanamineinstead of the (2,4-dimethoxyphenyl)methanamine. A beige powder wasobtained (46 mg, 0.11 mmol, 62%). ESI-MS (m/z): 436 [M+H]⁺.

Example 5:(S)—N-(1-(4-Bromophenyl)ethyl)-1-(2,4-difluorobenzyl)-1H-indole-5-carboxamide

The title compound was prepared following the same general protocol asdescribed in Step 4, Example 1, using (S)-1-(4-bromophenyl)ethanamineinstead of the (2,4-dimethoxyphenyl)methanamine. A white powder wasobtained (50 mg, 0.11 mmol, 63%). ESI-MS (m/z): 469/471 [M+H]⁺.

Example 6:N-(Chroman-3-yl)-1-(2,4-difluorobenzyl)-1H-indole-5-carboxamide

The title compound was prepared following the same general protocol asdescribed in Step 4, Example 1, using chroman-3-amine instead of the(2,4-dimethoxyphenyl)methanamine. A white powder was obtained (52 mg,0.12 mmol, 73%). ESI-MS (m/z): 419 [M+H]⁺.

Example 7:(R)—N-(1-(4-Bromophenyl)ethyl)-1-(2,4-difluorobenzyl)-1H-indole-5-carboxamide

The title compound was prepared following the same general protocol asdescribed in Step 4, Example 1, using (R)-1-(4-bromophenyl)ethanamineinstead of the (2,4-dimethoxyphenyl)methanamine. A white powder wasobtained (55 mg, 0.12 mmol, 69%). ESI-MS (m/z): 469/471 [M+H]⁺.

Example 8:1-(2,4-Difluorobenzyl)-N-(1-phenylpropyl)-1H-indole-5-carboxamide

The title compound was prepared following the same general protocol asdescribed in Step 4, Example 1, using 1-phenylpropan-1-amine instead ofthe (2,4-dimethoxyphenyl)methanamine. A beige powder was obtained (46mg, 0.12 mmol, 67%). ESI-MS (m/z): 405 [M+H]⁺.

Example 9: N-Benzyl-1-(2,4-difluorobenzyl)-1H-indole-5-carboxamide

The title compound was prepared following the same general protocol asdescribed in Step 4, Example 1, using phenylmethanamine instead of the(2,4-dimethoxyphenyl)methanamine. A light green powder was obtained (49mg, 0.13 mmol, 77%). ESI-MS (m/z): 377 [M+H]⁺.

Example 10:(R)-1-(2,4-Difluorobenzyl)-N-(1-(4-nitrophenyl)ethyl)-1H-indole-5-carboxamide

The title compound was prepared following the same general protocol asdescribed in Step 4, Example 1, using (R)-1-(4-nitrophenyl)ethanamineinstead of the (2,4-dimethoxyphenyl)methanamine. A beige powder wasobtained (45 mg, 0.10 mmol, 60%). ESI-MS (m/z): 436 [M+H]⁺.

Example 11:1-(2,4-Difluorobenzyl)-N-(2-phenylpropan-2-yl)-1H-indole-5-carboxamide

To a solution of 1-(2,4-difluorobenzyl)-1H-indole-5-carboxylic acid (50mg, 0.17 mmol, 1 equiv) in DCM (2 mL) was added 2-phenylpropane-2-amine(27 μL, 0.18 mmol, 1.05 equiv), DIEA (30 μL, 0.17 mmol, 1 equiv) andHATU (68 mg, 0.18 mmol, 1.05 equiv). The reaction mixture was stirred 2h at room temperature. The solvent was removed in vacuo. The residue wasdissolved in AcOEt and washed with a 0.5N HCl aqueous solution, asaturated NaHCO₃ solution and brine, dried over MgSO₄ and concentratedin vacuo to afford a white powder (63 mg, 0.15 mmol, 92%). ESI-MS (m/z):405 [M+H]⁺.

Example 12:1-(2,4-Difluorobenzyl)-N-(thiophen-2-ylmethyl)-1H-indole-5-carboxamide

The title compound was prepared following the same general protocol asdescribed in Step 4, Example 1, using thiophen-2-ylmethanamine insteadof the (2,4-dimethoxyphenyl)methanamine. A white powder was obtained (45mg, 0.12 mmol, 69%). ESI-MS (m/z): 383 [M+H]⁺.

Example 13:1-(2,4-Difluorobenzyl)-N-(2-methoxyethyl)-1H-indole-5-carboxamide

The title compound was prepared following the same general protocol asdescribed in Step 4, Example 1, using 2-methoxyethanamine instead of the(2,4-dimethoxyphenyl)methanamine. A light green powder was obtained (47mg, 0.14 mmol, 80%). ESI-MS (m/z): 345 [M+H]⁺.

Example 14:1-(2,4-Difluorobenzyl)-N-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-1H-indole-5-carboxamide

The title compound was prepared following the same general protocol asdescribed in Step 4, Example 1, using(2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methanamine instead of the(2,4-dimethoxyphenyl)methanamine. A beige powder was obtained (65 mg,0.15 mmol, 88%). ESI-MS (m/z): 435 [M+H]⁺.

Example 15:1-(2,4-Difluorobenzyl)-N-(1-(naphthalen-1-yl)ethyl)-1H-indole-5-carboxamide

The title compound was prepared following the same general protocol asdescribed in Step 4, Example 1, using 1-(naphthalen-1-yl)ethanamineinstead of the (2,4-dimethoxyphenyl)methanamine. A white powder wasobtained (55 mg, 0.12 mmol, 73%). ESI-MS (m/z): 441 [M+H]⁺.

Example 16:(S)-1-(2,4-Difluorobenzyl)-N-(1-(4-fluorophenyl)ethyl)-1H-indole-5-carboxamide

The title compound was prepared following the same general protocol asdescribed in Step 4, Example 1, using (S)-1-(4-fluorophenyl)ethanamineinstead of the (2,4-dimethoxyphenyl)methanamine. A white powder wasobtained (45 mg, 0.11 mmol, 65%). ESI-MS (m/z): 409 [M+H]⁺.

Example 17:(R)-1-(2,4-Difluorobenzyl)-N-(1-(4-fluorophenyl)ethyl)-1H-indole-5-carboxamide

The title compound was prepared following the same general protocol asdescribed in Step 4, Example 1, using (R)-1-(4-fluorophenyl)ethanamineinstead of the (2,4-dimethoxyphenyl)methanamine. A white powder wasobtained (41 mg, 0.10 mmol, 59%). ESI-MS (m/z): 409 [M+H]⁺.

Example 18: N-Cyclopentyl-1-(2,4-difluorobenzyl)-1H-indole-5-carboxamide

The title compound was prepared following the same general protocol asdescribed in Step 4, Example 1, using cyclopentanamine instead of the(2,4-dimethoxyphenyl)methanamine. A white powder was obtained (35 mg,0.10 mmol, 58%). ESI-MS (m/z): 355 [M+H]⁺.

Example 19:1-(2,4-Difluorobenzyl)-N-((1R,2S)-2-phenylcyclopropyl)-1H-indole-5-carboxamide

The title compound was prepared following the same general protocol asdescribed in Step 4, Example 1, using (1R,2S)-2-phenylcyclopropanamineinstead of the (2,4-dimethoxyphenyl)methanamine. A beige powder wasobtained (49 mg, 0.12 mmol, 72%). ESI-MS (m/z): 403 [M+H]⁺.

Example 20:N-(4-Aminobenzyl)-1-(2,4-difluorobenzyl)-1H-indole-5-carboxamide

The title compound was prepared following the same general protocol asdescribed in Example 11, using 4-(aminomethyl)aniline instead of the2-phenylpropane-2-amine. A yellow powder was obtained (19 mg, 0.05 mmol,29%). ESI-MS (m/z): 392 [M+H]⁺.

Example 21:1-(2,4-difluorobenzyl)-2,3-dimethyl-N-(1-phenylpropyl)-1H-indole-5-carboxamide

Step 1: Ethyl1-(2,4-difluorobenzyl)-2,3-dimethyl-1H-indole-5-carboxylate

NaH (1.1 equiv) was added to a solution of ethyl2,3-dimethyl-1H-indole-5-carboxylate in DMF at room temperature. After30 min, 2,4-difluorobenzyl bromide (1.1 equiv) was added to the reactionmixture and stirred for 1 h. After the reaction was completed, thesolvent was removed in vacuo to obtain the crude which was purified byflash chromatography to obtain the compound. LC-MS 344 (M+H).

Step 2: 1-(2,4-difluorobenzyl)-2,3-dimethyl-1H-indole-5-carboxylic Acid

A mixture of above compound and NaOH (10 equiv) in EtOH was refluxed at100° C. for 2 h. The reaction mixture was cooled to rt, then acidifiedto pH-4 with sat′d citric acid. The mixture was evaporated in vacuo toobtain the crude, which was precipitated in water and filtered to obtainthe compound. LC-MS 316 (M+H).

Step 3:1-(2,4-difluorobenzyl)-2,3-dimethyl-N-(1-phenylpropyl)-1H-indole-5-carboxamide

To a mixture of1-(2,4-difluorobenzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid in DMFwas added DIPEA (1.3 equiv) and HATU (1.2 equiv). The mixture wasstirred for 5 min, and then α-ethylbenzylamine (1.1 equiv) was added.The reaction mixture was stirred at rt for 1 h. After the reaction wascompleted, the solvent was removed in vacuo to obtain the crude whichwas purified by flash chromatography to obtain the title compound. LC-MS433 (M+H).

Example 22:1-(4-chlorobenzyl)-2,3-dimethyl-N-(1-phenylpropyl)-1H-indole-5-carboxamide

The title compound was prepared following the same general protocol asdescribed in Steps 1, 2, and 3 of Example 21, using4-chloro-benzylchloride and ethyl 2,3-dimethyl-1H-indole-5-carboxylate.LC-MS 431 (M+H).

Example 24:1-(3-chlorophenethyl)-N-(1-phenylpropyl)-1H-indole-5-carboxamide

The title compound was prepared following the same general protocol asdescribed in Step 1 of Example 21, using 2-(3-chlorophenyl)ethylchloride and N-(1-phenylpropyl)-1H-indole-5-carboxamide. LC-MS 417(M+H).

Example 25: 1-benzoyl-N-(1-phenylpropyl)-1H-indole-5-carboxamide

Benzoyl chloride (1.1 equiv) was added to a solution ofN-(1-phenylpropyl)-1H-indole-5-carboxamide in CH₂Cl₂, Et₃N (1.3 equiv)at room temperature. After the reaction was completed, the solvent wasevaporated and the residual was purified by silica gel columnchromatography to get the product. LC-MS 383 (M+H).

Example 26:1-(4-nitrobenzoyl)-N-(1-phenylpropyl)-1H-indole-5-carboxamide

The title compound was prepared following the same general protocol asdescribed in Example 25, using 4-nitrobenzoylchloride andN-(1-phenylpropyl)-1H-indole-5-carboxamide. LC-MS 428 (M+H).

Example 27:1-(2,3-difluorobenzoyl)-N-(1-phenylpropyl)-1H-indole-5-carboxamide

The title compound was prepared following the same general protocol asdescribed in Example 25, using 2,3-difluorobenzoylchloride andN-(1-phenylpropyl)-1H-indole-5-carboxamide. LC-MS 419 (M+H).

Example 28: N-(1-phenylpropyl)-1-tosyl-1H-indole-5-carboxamide

Tosyl chloride (1.1 equiv), benzyltriethylammonium chloride (0.5 equiv)was added to a solution of N-(1-phenylpropyl)-1H-indole-5-carboxamide inCH₂Cl₂, KOH (1.3 equiv) at room temperature. After the reaction wascompleted, the solvent was evaporated and the residual was purified bysilica gel column chromatography to get the product. LC-MS 433 (M+H).

Example 30:1-(naphthalen-1-ylsulfonyl)-N-(1-phenylpropyl)-1H-indole-5-carboxamide

The title compound was prepared following the same general protocol asdescribed in Example 28, using 1-naphthyl sulfonyl chloride andN-(1-phenylpropyl)-1H-indole-5-carboxamide. LC-MS 469 (M+H).

Example 31:1-(4-nitrophenylsulfonyl)-N-(1-phenylpropyl)-1H-indole-5-carboxamide

The title compound was prepared following the same general protocol asdescribed in Example 28, using 4-nitrophenylsulfonyl chloride andN-(1-phenylpropyl)-1H-indole-5-carboxamide. LC-MS 464 (M+H).

Example 32:1-((6-chloropyridin-3-yl)methyl)-N-(1-phenylpropyl)-1H-indole-5-carboxamide

The title compound was prepared following the same general protocol asdescribed in Step 1, Example 21, using 5-(bromomethyl)-2-chloropyridineand N-(1-phenylpropyl)-1H-indole-5-carboxamide. LC-MS 404 (M+H).

Examples 33, 34

The title compounds can be prepared analogously to Example 35, below,but substituting

This bromomethyl compound can be prepared as described in Example 35,step 2, below, substituting methyl 1-methyl-1-(p-tolyl)-propionate formethyl 1-(p-tolyl)cyclopropanecarboxylate in the bromination reaction.Alternatively the bromomethyl compound can be purchased from ChingluPharmaceutical Research LLC, 705 North Mountain Rd., Suite C115,Newington, Conn.

Various compounds such as 33 and 34 can then be prepared, as is apparentto a person of skill in the art, by use of the appropriate precursorsand reagents as indicated in Example 35, steps 3-8.

Example 35:(S)-1-(4-((5-((1-(3-Isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenyl)cyclopropanecarboxylicAcid

Step 1: Methyl 1-(p-tolyl)cyclopropanecarboxylate

To a solution of 1-(p-tolyl)cyclopropanecarboxylic acid (900 mg, 5.1mmol) in acetonitrile (20 mL) was added DBU (917 μL) followed by methyliodide (1.91 mL). The resulting solution was heated at reflux overnight,and then diluted with AcOEt. The mixture was washed with a 0.5 N HClsolution, a saturated solution of NaHCO₃, and brine, dried on MgSO₄, andconcentrated. The resulting colorless oil was purified by chromatographyon silica gel (Hexane/ethyl acetate 9/1) to afford the title compound asa colorless oil (622 mg, 64%).

Step 2: Methyl 1-(4-(bromomethyl)phenyl)cyclopropanecarboxylate

To a solution of methyl 1-(p-tolyl)cyclopropanecarboxylate (622 mg, 3.27mmol) in carbon tetrachloride (16 mL) was added N-bromosuccinimide (611mg) followed by benzoyl peroxide (40 mg). The resulting solution washeated at reflux overnight, and then diluted with methylene chloride.The mixture was washed with brine, dried on MgSO₄, and concentrated toafford a colorless oil (860 mg, 97%).

Step 3: 2,3-Dimethyl-1H-indole-5-carboxylic Acid

To a solution of ethyl 2,3-dimethyl-1H-indole-5-carboxylate (500 mg, 2.3mmol) in ethanol (10 mL) was added a 5N NaOH solution (9.2 mL). Theresulting solution was heated at 50° C. for 4 h, and then quenchedcarefully by addition of a 6N HCl solution (10 mL). The mixture wasdiluted with ethyl acetate, washed with a 0.5 N HCl solution and brine,dried on MgSO₄, and concentrated to afford a yellow powder (500 mg,100%). ESI-MS (m/z): 190 [MH]⁺

Step 4:1-(4-(1-(Methoxycarbonyl)cyclopropyl)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicAcid

To a solution of 2,3-dimethyl-1H-indole-5-carboxylic acid (500 mg, 2.3mmol) in anhydrous DMF (20 mL) was added methyl1-(4-(bromomethyl)phenyl)cyclopropanecarboxylate (620 mg) followed byNaH (230 mg). The resulting solution was allowed to stir overnight underargon atmosphere. The remaining NaH was hydrolyzed by the carefuladdition of a 0.5 N HCl solution. The mixture was diluted with ethylacetate, washed with a 0.5 N HCl solution and brine, dried on MgSO₄, andconcentrated. The crude residue was purified by chromatography on silicagel (Hexane/Ethyl acetate 5/5) to afford an orange powder (361 mg).ESI-MS (m/z): 378 [MH]⁺

Step 5: (S)-Methyl1-(4-((5-((1-(3-bromophenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenyl)cyclopropanecarboxylate

To a solution of1-(4-(1-(methoxycarbonyl)cyclopropyl)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid (50 mg, 0.13 mmol) in DMF (1 mL) was added(S)-1-(3-bromophenyl)ethylamine (21 DIEA (45 μL) and HATU (54 mg). Thereaction mixture was allowed to stir at rt for 30 min, and then wasdiluted by ethyl acetate. The resulting mixture was washed with a 0.5 NHCl solution, a saturated solution of NaHCO₃, and brine, dried on MgSO₄,and concentrated to afford a yellow oil (73 mg) which was directly usedwithout further purification. ESI-MS (m/z): 559/561 [MH]⁺

Step 6: (S)-Methyl1-(4-((2,3-dimethyl-5-((1-(3-(prop-1-en-2-yl)phenyl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)phenyl)cyclopropanecarboxylate

To a solution of (S)-methyl1-(4-((5-((1-(3-bromophenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenyl)cyclopropanecarboxylate(73 mg) in dioxane/water (1.2 mL/0.3 mL) was added isopropenylboronicacid pinacol ester (49 K₂CO₃ (36 mg) and Pd(PPh₃)₄ (15 mg). The solutionwas degassed with argon and then stirred for 1 h at 100° C. undermicrowave. The resulting mixture was diluted with ethyl acetate washedwith a 0.5 N HCl solution, a saturated solution of NaHCO₃, and brine,dried on MgSO₄, and concentrated to afford a yellow oil which wasdirectly used without further purification. ESI-MS (m/z): 521 [MH]⁺

Step 7: (S)-Methyl1-(4-((5-((1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenyl)cyclopropanecarboxylate

To a solution of (S)-methyl1-(4-((2,3-dimethyl-5-((1-(3-(prop-1-en-2-yl)phenyl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)phenyl)cyclopropanecarboxylatein EtOH (5 mL) was added Pd/C 10%. The resulting mixture was stirred for5 h under hydrogen atmosphere. The solution was then filtered andconcentrated to afford a yellow oil which was directly used withoutfurther purification. ESI-MS (m/z): 523 [MH]⁺

Step 8:(S)-1-(4-((5-((1-(3-Isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenyl)cyclopropanecarboxylicAcid

To a solution of(S)-1-(4-((5-((1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenyl)cyclopropanecarboxylicacid in methanol (1 mL) was added a 5 N NaOH solution (1 mL). Theresulting solution was heated at 50° C. for 4 h, and then quenchedcarefully by addition of a 6 N HCl solution (1 mL). The mixture wasdiluted with ethyl acetate, washed with a 0.5 N HCl solution and brine,dried on MgSO₄, and concentrated. The resulting oil was purified bypreparative HPLC to afford a white powder (9 mg). ESI-MS (m/z): 509[MH]⁺

Example 36:(S)-2-(4-(((5-((1-(3-Cyclopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)aceticAcid

Step 1: Methyl 2-(p-tolyloxy)acetate

To a solution of p-cresol (2 mL, 19.1 mmol) in anhydrous DMF (50 mL)were added Cs₂CO₃ (8.1 g, 24.9 mmol) and methyl bromoacetate (1.9 mL,20.1 mmol). The suspension was stirred at room temperature for 3 h.After dilution with ethyl acetate, the reaction mixture was washed witha 0.5 N HCl solution, a saturated solution of NaHCO₃, and brine, driedon MgSO₄, and concentrated. The resulting oil was purified bychromatography on silica gel (Hexane/ethyl acetate 8/2) to afford thetitle compound as a colorless oil (3.10 g, 90%).

Step 2: Methyl 2-(4-(bromomethyl)phenoxy)acetate

To a solution of the methyl 2-(p-tolyloxy)acetate (3.10 g, 17.2 mmol) incarbon tetrachloride (60 mL) was added N-bromosuccinimide (3.57 g, 20mmol) followed by benzoyl peroxide (463 mg, 1.9 mmol). The resultingsolution was heated at reflux overnight, and then diluted with methylenechloride. The mixture was washed with brine, dried on MgSO₄, andconcentrated. The resulting colorless oil was purified by chromatographyon silica gel (Hexane/ethyl acetate 9/1) to afford a colorless oil (2.5g, 56%).

Step 3: Allyl1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylate

To a solution of the allyl 2,3-dimethyl-1H-indole-5-carboxylate (500 mg,2.2 mmol) in anhydrous DMF (20 mL) was added the methyl2-(4-(bromomethyl)phenoxy)acetate (565 mg, 2.2 mmol) followed by NaH(131 mg, 3.3 mmol). The resulting solution was allowed to stir overnightunder argon atmosphere. The remaining NaH was hydrolyzed by the carefuladdition of a 0.5 N HCl solution. The mixture was diluted with ethylacetate, washed with a 0.5 N HCl solution and brine, dried on MgSO₄, andconcentrated. The crude residue was purified by chromatography on silicagel (Hexane/Ethyl acetate 5/5) to afford yellow oil (536 mg, 61%).ESI-MS (m/z): 408 [M+H]⁺.

Step 4:1-(4-(2-Methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicAcid

A solution of the allyl1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylate(536 mg, 1.3 mmol) and morpholine (1.14 mL, 13.2 mmol) in anhydrous THFwas degassed with argon. Then Pd(PPh₃)₄ (152 mg, 0.13 mmol) was addedand the reaction stirred under argon protection for 1.5 h. The reactionmixture was diluted with ethyl acetate, washed with brine, concentrated.The title compound was precipitated in ethyl ether as a beige powder(430 mg, 89%). ESI-MS (m/z): 368 [M+H]⁺.

Step 5: (S)-Methyl2-(4-((5-((1-(3-cyclopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)acetate

To a solution of the1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid (50 mg, 0.14 mmol) in DCM (1 mL) was added the(S)-1-(3-cyclopropylphenyl)ethanamine hydrochloride (28 mg), DIEA (73μL) and HATU (53 mg). The reaction mixture was allowed to stir at rt for30 min, and then was diluted by ethyl acetate. The resulting mixture waswashed with a 0.5 N HCl solution, a saturated solution of NaHCO₃, andbrine, dried on MgSO₄, and concentrated to afford a yellow oil (73 mg)which was directly used without further purification. ESI-MS (m/z): 497[M+H]⁺

Step 6:(S)-2-(4-((5-((1-(3-Cyclopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)aceticAcid

To a solution of the (S)-methyl2-(4-((5-((1-(3-cyclopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)acetatein methanol (1 mL) was added a 5N NaOH solution (1 mL). The resultingsolution was heated at 50° C. for 4 h, and then quenched carefully byaddition of a 6N HCl solution (1 mL). The mixture was diluted with ethylacetate, washed with a 0.5 N HCl solution and brine, dried on MgSO₄, andconcentrated. The resulting oil was purified by preparative HPLC toafford a white powder (46 mg). ESI-MS (m/z): 497 [MH]⁺

Example 37:(S)-2-(4-(((5-((1-(3-Isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)aceticAcid

Step 1: (S)-Methyl2-(4-((5-((1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)acetate

The title compound was prepared following the same protocol as describedin Step 5, Example 36, using the (S)-1-(3-isopropylphenyl)ethanaminehydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanaminehydrochloride.

Step 2:(S)-2-(4-((5-((1-(3-Isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)aceticAcid

The title compound was prepared following the same protocol as describedin Step 6, Example 36, using the (S)-methyl2-(4-((5-((1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)acetateinstead of the (S)-methyl2-(4-((5-((1-(3-cyclopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)acetate.ESI-MS (m/z): 499 [MH]⁺

Example 38:(S)-2-(4-(((5-((1-(4-(tert-Butyl)phenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)aceticAcid

Step 1: (S)-Methyl2-(4-((5-((1-(4-(tert-butyl)phenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)acetate

The title compound was prepared following the same protocol as describedin Step 5, Example 36, using the (S)-1-(4-(tert-butyl)phenyl)ethanaminehydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanaminehydrochloride.

Step 2:(S)-2-(4-((5-((1-(4-(tert-Butyl)phenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)aceticAcid

The title compound was prepared following the same protocol as describedin Step 6, Example 36, using the (S)-methyl2-(4-((5-((1-(4-(tert-butyl)phenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)acetateinstead of the (S)-methyl2-(4-((5-((1-(3-cyclopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)acetate.ESI-MS (m/z): 513 [MH]⁺.

Example 39:(S)-2-(3-((5-((1-(3-Cyclopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)aceticAcid

Step 1: Methyl 2-(m-tolyloxy)acetate

The title compound was prepared following the same protocol as describedin Step 1, Example 36, using the m-cresol instead of the p-cresol.

Step 2: Methyl 2-(3-(bromomethyl)phenoxy)acetate

The title compound was prepared following the same protocol as describedin Step 2, Example 36, using the methyl 2-(m-tolyloxy)acetate instead ofthe methyl 2-(p-tolyloxy)acetate.

Step 3: Allyl1-(3-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylate

The title compound was prepared following the same general protocol asdescribed in Step 3, Example 36, using the methyl2-(3-(bromomethyl)phenoxy)acetate instead of the methyl2-(4-(bromomethyl)phenoxy)acetate. ESI-MS (m/z): 408 [M+H]⁺.

Step 4:1-(3-(2-Methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 4, Example 36, using the allyl1-(3-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylateinstead of the allyl1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylate.ESI-MS (m/z): 368 [M+H]⁺.

Step 5: (S)-Methyl2-(3-((5-((1-(3-cyclopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)acetate

The title compound was prepared following the same protocol as describedin Step 5, Example 36, using the1-(3-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid instead of the1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid.

Step 6:(S)-2-(3-((5-((1-(3-Cyclopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)aceticAcid

The title compound was prepared following the same protocol as describedin Step 6, Example 36, using the (S)-methyl2-(3-((5-((1-(3-cyclopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)acetateinstead of the (S)-methyl2-(4-((5-((1-(3-cyclopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)acetate.ESI-MS (m/z): 497 [MH]⁺

Example 40:(S)-2-(3-((5-((1-(3-Isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)aceticAcid

Step 1: (S)-Methyl2-(3-((5-((1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)acetate

The title compound was prepared following the same protocol as describedin Step 5, Example 36, using the (S)-1-(3-isopropylphenyl)ethanaminehydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanaminehydrochloride and the1-(3-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid instead of the1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid.

Step 2:(S)-2-(3-((5-((1-(3-Isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)aceticAcid

The title compound was prepared following the same protocol as describedin Step 6, Example 36, using the (S)-methyl2-(3-((5-((1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)acetateinstead of the (S)-methyl2-(4-((5-((1-(3-cyclopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)acetate.ESI-MS (m/z): 499 [MH]⁺.

Example 41:(S)-2-(3-((5-((1-(4-(tert-Butyl)phenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)aceticAcid

Step 1: (S)-Methyl2-(3-((5-((1-(4-(tert-butyl)phenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)acetate

The title compound was prepared following the same protocol as describedin Step 5, Example 36, using the (S)-1-(4-(tert-butyl)phenyl)ethanaminehydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanaminehydrochloride and the1-(3-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid instead of the1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid.

Step 2:(S)-2-(3-((5-((1-(4-(tert-Butyl)phenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)aceticAcid

The title compound was prepared following the same protocol as describedin Step 6, Example 36, using the (S)-methyl2-(3-((5-((1-(4-(tert-butyl)phenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)acetateinstead of the (S)-methyl2-(4-((5-((1-(3-cyclopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)acetate.ESI-MS (m/z): 513 [M+H]⁺.

Example 42:(R)-2-(3-((5-(((S)-1-(3-Isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoicAcid

Step 1: (R)-Methyl 2-(m-tolyloxy)propanoate

To a solution of the m-cresol (1.0 g, 9.2 mmol) in anhydrous THF (15 mL)at 0° C. under argon protection was added triphenylphosphine (2.55 g,9.7 mmol), followed by addition of the (S)-methyl 2-hydroxypropanoate(926 μL, 9.7 mmol). Then diisopropylazodicarboxylate (DIAD) (2.85 mL,13.8 mmol) was added dropwise at 0° C. The reaction mixture was stirredat room temperature overnight. The resulting mixture was diluted byethyl acetate, washed with a 0.5 N HCl solution, a saturated solution ofNaHCO₃, and brine, dried on MgSO₄, and concentrated. The obtained oilwas purified by flash chromatography (Hexane/Ethyl acetate 0-50%) toafford a colorless oil (820 mg, 46%).

Step 2: (R)-Methyl 2-(3-(bromomethyl)phenoxy)propanoate

The title compound was prepared following the same protocol as describedin Step 2, Example 36, using the (R)-methyl 2-(m-tolyloxy)propanoateinstead of the methyl 2-(p-tolyloxy)acetate.

Step 3: (R)-Allyl1-(3-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylate

The title compound was prepared following the same general protocol asdescribed in Step 3, Example 36, using the (R)-methyl2-(3-(bromomethyl)phenoxy)propanoate instead of the methyl2-(4-(bromomethyl)phenoxy)acetate. ESI-MS (m/z): 422 [M+H]⁺.

Step 4:(R)-1-(3-((1-Methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 4, Example 36, using the (R)-allyl1-(3-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylateinstead of the allyl1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylate.ESI-MS (m/z): 368 [M+H]⁺.

Step 5: (R)-Methyl2-(3-((5-(((S)-1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoate

The title compound was prepared following the same protocol as describedin Step 5, Example 36, using the (S)-1-(3-isopropylphenyl)ethanaminehydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanaminehydrochloride and the(R)-1-(3-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid instead of the1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid.

Step 6:(R)-2-(3-((5-(((S)-1-(3-Isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoicAcid

The title compound was prepared following the same protocol as describedin Step 6, Example 36, using the (R)-methyl2-(3-((5-(((S)-1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoateinstead of the (S)-methyl2-(4-((5-((1-(3-cyclopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)acetate.ESI-MS (m/z): 513 [MH]⁺

Example 43:(R)-2-(3-((5-(((S)-1-(4-(tert-Butyl)phenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoicAcid

Step 1: (R)-Methyl2-(3-((5-(((S)-1-(4-(tert-butyl)phenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoate

The title compound was prepared following the same protocol as describedin Step 5, Example 36, using the (S)-1-(4-(tert-butyl)phenyl)ethanaminehydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanaminehydrochloride and the(R)-1-(3-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid instead of the1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid.

Step 2:(R)-2-(3-((5-(((S)-1-(4-(tert-Butyl)phenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoicAcid

The title compound was prepared following the same protocol as describedin Step 6, Example 36, using the (R)-methyl2-(3-((5-(((S)-1-(4-(tert-butyl)phenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoateinstead of the (S)-methyl2-(4-((5-((1-(3-cyclopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)acetate.ESI-MS (m/z): 527 [MH]⁺.

Example 44:(S)-2-(3-((5-(((S)-1-(3-Isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoicAcid

Step 1: (S)-Methyl 2-(m-tolyloxy)propanoate

The title compound was prepared following the same protocol as describedin Step 1, Example 42, using the (R)-methyl 2-hydroxypropanoate insteadof the (S)-methyl 2-hydroxypropanoate.

Step 2: (S)-Methyl 2-(3-(bromomethyl)phenoxy)propanoate

The title compound was prepared following the same protocol as describedin Step 2, Example 36, using the (S)-methyl 2-(m-tolyloxy)propanoateinstead of the methyl 2-(p-tolyloxy)acetate.

Step 3: (S)-Allyl1-(3-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylate

The title compound was prepared following the same general protocol asdescribed in Step 3, Example 36, using the (S)-methyl2-(3-(bromomethyl)phenoxy)propanoate instead of the methyl2-(4-(bromomethyl)phenoxy)acetate. ESI-MS (m/z): 422 [M+H]⁺.

Step 4:(S)-1-(3-((1-Methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 4, Example 36, using the (S)-allyl1-(3-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylateinstead of the allyl1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylate.ESI-MS (m/z): 368 [M+H]⁺.

Step 5: (S)-Methyl2-(3-((5-(((S)-1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoate

The title compound was prepared following the same protocol as describedin Step 5, Example 36, using the (S)-1-(3-isopropylphenyl)ethanaminehydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanaminehydrochloride and the(S)-1-(3-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid instead of the1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid.

Step 6:(S)-2-(3-((5-(((S)-1-(3-Isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoicAcid

The title compound was prepared following the same protocol as describedin Step 6, Example 36, using the (S)-methyl2-(3-((5-(((S)-1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoateinstead of the (S)-methyl2-(4-((5-((1-(3-cyclopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)acetate.ESI-MS (m/z): 513 [M+H]⁺

Example 45:(S)-2-(3-((5-(((S)-1-(4-(tert-Butyl)phenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoicAcid

Step 1: (S)-Methyl2-(3-((5-(((S)-1-(4-(tert-butyl)phenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoate

The title compound was prepared following the same protocol as describedin Step 5, Example 36, using the (S)-1-(4-(tert-Butyl)phenyl)ethanaminehydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanaminehydrochloride and the(S)-1-(3-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid instead of the1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid.

Step 2:(S)-2-(3-((5-(((S)-1-(4-(tert-Butyl)phenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoicAcid

The title compound was prepared following the same protocol as describedin Step 6, Example 36, using the (S)-methyl2-(3-((5-(((S)-1-(4-(tert-Butyl)phenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoateinstead of the (S)-methyl2-(4-((5-((1-(3-cyclopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)acetate.ESI-MS (m/z): 527 [MH]⁺

Example 46:(S)-2-(3-((5-(((S)-1-(3-Cyclopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoicAcid

Step 1: (S)-Methyl2-(3-((5-(((S)-1-(3-cyclopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoate

The title compound was prepared following the same protocol as describedin Step 5, Example 36, using the(S)-1-(3-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid instead of the1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid.

Step 2:(S)-2-(3-((5-(((S)-1-(3-Cyclopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoicAcid

The title compound was prepared following the same protocol as describedin Step 6, Example 36, using the (S)-methyl2-(3-((5-(((S)-1-(3-cyclopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoateinstead of the (S)-methyl2-(4-((5-((1-(3-cyclopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)acetate.ESI-MS (m/z): 511 [MH]⁺.

Example 47:(S)-2-(3-((5-((1-(3-Isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)-2-methylpropanoicAcid

Step 1: Methyl 2-methyl-2-(m-tolyloxy)propanoate

The title compound was prepared following the same protocol as describedin Step 1, Example 36, using the m-cresol instead of the p-cresol andthe methyl α-bromoisobutyrate instead of the methyl bromoacetate.

Step 2: Methyl 2-(3-(bromomethyl)phenoxy)-2-methylpropanoate

The title compound was prepared following the same protocol as describedin Step 2, Example 36, using the methyl2-methyl-2-(m-tolyloxy)propanoate instead of the methyl2-(p-tolyloxy)acetate.

Step 3: Allyl1-(3-((1-methoxy-2-methyl-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylate

The title compound was prepared following the same general protocol asdescribed in Step 3, Example 36, using the methyl2-(3-(bromomethyl)phenoxy)-2-methylpropanoate instead of the methyl2-(4-(bromomethyl)phenoxy)acetate. ESI-MS (m/z): 436 [M+H]⁺.

Step 4:1-(3-((1-Methoxy-2-methyl-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 4, Example 36, using the allyl1-(34(1-methoxy-2-methyl-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylateinstead of the allyl1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylate.ESI-MS (m/z): 396 [M+H]⁺.

Step 5: (S)-Methyl2-(3-((5-((1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)-2-methylpropanoate

The title compound was prepared following the same protocol as describedin Step 5, Example 36, using the (S)-1-(3-isopropylphenyl)ethanaminehydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanaminehydrochloride and the1-(3-((1-methoxy-2-methyl-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid instead of the1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid.

Step 6:(S)-2-(3-((5-((1-(3-Isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)-2-methylpropanoicAcid

The title compound was prepared following the same protocol as describedin Step 6, Example 36, using the (S)-methyl2-(3-((5-((1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)-2-methylpropanoateinstead of the (S)-methyl2-(4-((5-((1-(3-cyclopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)acetate.ESI-MS (m/z): 527 [MH]⁺

Example 48:(S)-2-(3-((5-((1-(4-(tert-Butyl)phenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)-2-methylpropanoicAcid

Step 1: (S)-Methyl2-(3-((5-((1-(4-(tert-butyl)phenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)-2-methylpropanoate

The title compound was prepared following the same protocol as describedin Step 5, Example 36, using the (S)-1-(4-(tert-butyl)phenyl)ethanaminehydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanaminehydrochloride and the1-(3-((1-methoxy-2-methyl-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid instead of the1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid.

Step 2:(S)-2-(3-((5-((1-(4-(tert-Butyl)phenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)-2-methylpropanoicAcid

The title compound was prepared following the same protocol as describedin Step 6, Example 36, using the (S)-methyl2-(3-((5-((1-(4-(tert-butyl)phenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)-2-methylpropanoateinstead of the (S)-methyl2-(4-((5-((1-(3-cyclopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)acetate.ESI-MS (m/z): 541 [MH]⁺.

Example 49:(S)-1-(3-(Cyanomethoxy)benzyl)-N-(1-(3-isopropylphenyl)ethyl)-2,3-dimethyl-1H-indole-5-carboxamide

Step 1: 2-(m-Tolyloxy)acetonitrile

The title compound was prepared following the same protocol as describedin Step 1, Example 36, using the m-cresol instead of the p-cresol andthe bromoacetonitrile instead of the methyl bromoacetate.

Step 2: 2-(3-(Bromomethyl)phenoxy)acetonitrile

The title compound was prepared following the same protocol as describedin Step 2, Example 36, using the 2-(m-Tolyloxy)acetonitrile instead ofthe methyl 2-(p-tolyloxy)acetate.

Step 3: Allyl1-(3-(cyanomethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylate

The title compound was prepared following the same general protocol asdescribed in Step 3, Example 36, using the2-(3-(Bromomethyl)phenoxy)acetonitrile instead of the methyl2-(4-(bromomethyl)phenoxy)acetate. ESI-MS (m/z): 375 [M+H]⁺.

Step 4: 1-(3-(Cyanomethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 4, Example 36, using the allyl1-(3-(cyanomethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylate insteadof the allyl1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylate.ESI-MS (m/z): 335 [M+H]⁺.

Step 5:(S)-1-(3-(Cyanomethoxy)benzyl)-N-(1-(3-isopropylphenyl)ethyl)-2,3-dimethyl-1H-indole-5-carboxamide

The title compound was prepared following the same protocol as describedin Step 5, Example 36, using the (S)-1-(3-isopropylphenyl)ethanaminehydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanaminehydrochloride and the1-(3-(cyanomethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acidinstead of the1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. ESI-MS (m/z): 480 [M+H]⁺.

Example 50:(S)—N-(1-(4-(tert-Butyl)phenyl)ethyl)-1-(3-(cyanomethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxamide

The title compound was prepared following the same protocol as describedin Step 5, Example 36, using the (S)-1-(4-(tert-butyl)phenyl)ethanaminehydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanaminehydrochloride and the1-(3-(cyanomethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acidinstead of the1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. ESI-MS (m/z): 494 [M+H]⁺.

Example 51:(S)-2-(4-((5-(((S)-1-(3-Isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoicAcid

Step 1: (S)-Methyl 2-(p-tolyloxy)propanoate

The title compound was prepared following the same protocol as describedin Step 1, Example 42, using the p-cresol instead of the m-cresol andthe (R)-methyl 2-hydroxypropanoate instead of the (S)-methyl2-hydroxypropanoate.

Step 2: (S)-Methyl 2-(4-(bromomethyl)phenoxy)propanoate

The title compound was prepared following the same protocol as describedin Step 2, Example 36, using the (S)-methyl 2-(p-tolyloxy)propanoateinstead of the methyl 2-(p-tolyloxy)acetate.

Step 3: (S)-Allyl1-(4-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylate

The title compound was prepared following the same general protocol asdescribed in Step 3, Example 36, using the (S)-methyl2-(4-(bromomethyl)phenoxy)propanoate instead of the methyl2-(4-(bromomethyl)phenoxy)acetate. ESI-MS (m/z): 422 [M+H]⁺.

Step 4:(S)-1-(4-((1-Methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 4, Example 36, using the (S)-allyl1-(4-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylateinstead of the allyl1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylate.ESI-MS (m/z): 368 [M+H]⁺.

Step 5: (S)-Methyl2-(4-((5-(((S)-1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoate

The title compound was prepared following the same protocol as describedin Step 5, Example 36, using the (S)-1-(3-isopropylphenyl)ethanaminehydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanaminehydrochloride and the(S)-1-(4-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid instead of the1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid.

Step 6:(S)-2-(4-((5-(((S)-1-(4-Isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoicAcid

The title compound was prepared following the same protocol as describedin Step 6, Example 36, using the (S)-methyl2-(4-((5-(((S)-1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoateinstead of the (S)-methyl2-(4-((5-((1-(3-cyclopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)acetate.ESI-MS (m/z): 513 [MH]⁺

Example 52:(S)-2-(4-((5-(((S)-1-(3-Cyclopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoicAcid

Step 1: (S)-Methyl2-(4-((5-(((S)-1-(3-cyclopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoate

The title compound was prepared following the same protocol as describedin Step 5, Example 36, using the(S)-1-(4-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid instead of the1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid.

Step 2:(S)-2-(4-((5-(((S)-1-(3-Cyclopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoicAcid

The title compound was prepared following the same protocol as describedin Step 6, Example 36, using the (S)-methyl2-(4-((5-(((S)-1-(3-cyclopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoateinstead of the (S)-methyl2-(4-((5-((1-(3-cyclopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)acetate.ESI-MS (m/z): 511 [MH]⁺

Example 53:(R)-2-(4-((5-(((S)-1-(3-Isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoicAcid

Step 1: (R)-Methyl 2-(p-tolyloxy)propanoate

The title compound was prepared following the same protocol as describedin Step 1, Example 42, using the p-cresol instead of the m-cresol.

Step 2: (R)-Methyl 2-(4-(bromomethyl)phenoxy)propanoate

The title compound was prepared following the same protocol as describedin Step 2, Example 36, using the (R)-methyl 2-(p-tolyloxy)propanoateinstead of the methyl 2-(p-tolyloxy)acetate.

Step 3: (R)-Allyl1-(4-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylate

The title compound was prepared following the same general protocol asdescribed in Step 3, Example 36, using the (R)-methyl2-(4-(bromomethyl)phenoxy)propanoate instead of the methyl2-(4-(bromomethyl)phenoxy)acetate. ESI-MS (m/z): 422 [M+H]⁺.

Step 4:(R)-1-(4-((1-Methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 4, Example 36, using the (R)-allyl1-(4-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylateinstead of the allyl1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylate.ESI-MS (m/z): 368 [M+H]⁺.

Step 5: (R)-Methyl2-(4-((5-(((S)-1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoate

The title compound was prepared following the same protocol as describedin Step 5, Example 36, using the (S)-1-(3-isopropylphenyl)ethanaminehydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanaminehydrochloride and the(R)-1-(4-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid instead of the1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid.

Step 6:(R)-2-(3-((5-(((S)-1-(4-Isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoicAcid

The title compound was prepared following the same protocol as describedin Step 6, Example 36, using the (R)-methyl2-(4-((5-(((S)-1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoateinstead of the (S)-methyl2-(4-((5-((1-(3-cyclopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)acetate.ESI-MS (m/z): 513 [MH]⁺

Example 54:(S)-2-(4-(((5-((1-(3-Isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)-2-methylpropanoicAcid

Step 1: Methyl 2-methyl-2-(p-tolyloxy)propanoate

The title compound was prepared following the same protocol as describedin Step 1, Example 36, using the methyl α-bromoisobutyrate instead ofthe methyl bromoacetate.

Step 2: Methyl 2-(4-(bromomethyl)phenoxy)-2-methylpropanoate

The title compound was prepared following the same protocol as describedin Step 2, Example 36, using the methyl2-methyl-2-(p-tolyloxy)propanoate instead of the methyl2-(p-tolyloxy)acetate.

Step 3: Allyl1-(4-((1-methoxy-2-methyl-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylate

The title compound was prepared following the same general protocol asdescribed in Step 3, Example 36, using the methyl2-(4-(bromomethyl)phenoxy)-2-methylpropanoate instead of the methyl2-(4-(bromomethyl)phenoxy)acetate. ESI-MS (m/z): 436 [M+H]⁺.

Step 4:1-(4-((1-Methoxy-2-methyl-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 4, Example 36, using the allyl1-(4-((1-methoxy-2-methyl-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylateinstead of the allyl1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylate.ESI-MS (m/z): 396 [M+H]⁺.

Step 5: (S)-Methyl2-(4-((5-((1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)-2-methylpropanoate

The title compound was prepared following the same protocol as describedin Step 5, Example 36, using the (S)-1-(3-isopropylphenyl)ethanaminehydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanaminehydrochloride and the1-(4-((1-methoxy-2-methyl-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid instead of the1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid.

Step 6:(S)-2-(4-((5-((1-(3-Isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)-2-methylpropanoicAcid

The title compound was prepared following the same protocol as describedin Step 6, Example 36, using the (S)-methyl2-(4-((5-((1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)-2-methylpropanoateinstead of the (S)-methyl2-(4-((5-((1-(3-cyclopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)acetate.ESI-MS (m/z): 527 [MH]⁺

Example 55:(S)-2-(2-Chloro-5-((5-(((S)-1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoicAcid

Step 1: (S)-Methyl 2-(2-chloro-5-methylphenoxy)propanoate

To a solution of the 2-chloro-5-methylphenol (4.0 g, 28 mmol) inanhydrous THF (24 mL) at 0° C. under argon protection was addedtriphenylphosphine (9.5 g, 36.4 mmol), followed by addition of the(R)-methyl 2-hydroxypropanoate (3.89 g, 31 mmol). Then DIAD (8.2 mL, 42mmol) was added slowly to the solution at 0° C. The reaction mixture wasstirred at room temperature for 20 h. The solvent was removed and thecrude was purified by flash chromatography (AcOEt/hexane 0-30%) toobtain the title compound.

Step 2: (S)-Methyl 2-(5-(bromomethyl)-2-chlorophenoxy)propanoate

To (S)-methyl 2-(2-chloro-5-methylphenoxy)propanoate (2.4 g, 10.5 mmol)in CCl₄ (20 mL) was added NBS (1.92 g, 11.55 mmol) and AIBN (0.35 g, 2.1mmol). The mixture was refluxed overnight. The reaction mixture wascooled and the solvent was removed to obtain the crude. The crude waspurified by flash chromatography (AcOEt/Hexane 0˜30%) to obtain thetitle compound.

Step 3: (S)-Allyl1-(4-chloro-3-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylate

The title compound was prepared following the same general protocol asdescribed for the synthesis of the (5-allyl1-(2-chloro-5-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylate(Step 3, Example 26), using the (S)-methyl2-(5-(bromomethyl)-2-chlorophenoxy)propanoate instead of the (S)-methyl2-(3-(bromomethyl)-4-chlorophenoxy)propanoate ESI-MS (m/z): 456 [M+1]⁺.

Step 4:(S)-1-(4-Chloro-3-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed for the synthesis of the(S)-1-(2-chloro-5-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid (Step 4, Example 26), using the (S)-allyl1-(4-chloro-3-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylateinstead of the (S)-allyl1-(2-chloro-5-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylate.ESI-MS (m/z): 416 [M+1]⁺.

Step 5: (S)-Methyl2-(2-chloro-5-((5-(((S)-1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoate

The(S)-1-(4-chloro-3-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid (55 mg, 0.13 mmol), the (S)-1-(3-isopropylphenyl)ethanaminehydrochloride (37 mg, 0.19 mmol) and HATU (61 mg, 0.16 mmol) weredissolved in DMF (3 mL) and DIEA (0.1 mL). It was stirred for 15 h. Thesolution was filtered and purified by preparative HPLC.

Step 6:(S)-2-(2-Chloro-5-((5-(((S)-1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoicAcid

The (S)-methyl2-(2-chloro-5-((5-(((S)-1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoatewas dissolved in methanol (1.5 mL), DMSO (˜1.5 mL) and water (0.1 mL)then NaOH (2 N, 0.1 mL) was added dropwise. The reaction was monitoredby LC/MS. It was stirred until all the starting material was consumed(˜3 h). It was acidified with trifluoroacetic acid, filtered andpurified by preparative HPLC to yield the title compound. ESI-MS (m/z):547.1 [M+H]⁺.

Example 56:(S)-2-(2-Chloro-5-((5-(((S)-1-(3-cyclopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoicAcid

A similar procedure was followed as described in the previous example(Example 20) to yield the title compound. ESI-MS (m/z): 545.1 [M+H]⁺.

Example 57:(S)-2-(5-((5-(((S)-1-(4-Bromophenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-2-chlorophenoxy)propanoicAcid

A similar procedure was followed as described in the previous example(Example 20) using (S)-1-(4-bromophenyl)ethanamine to yield the titlecompound. ESI-MS (m/z): 585.0 [M+H]⁺.

Example 58:(S)-2-(5-((5-(((S)-1-(4-(tert-Butyl)phenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-2-chlorophenoxy)propanoicAcid

Step 1: (S)-Methyl2-(5-((5-(((S)-1-(4-(tert-butyl)phenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-2-chlorophenoxy)propanoate

The title compound was prepared following the same protocol as describedin Step 5, Example 36, using the (S)-1-(4-(tert-butyl)phenyl)ethanaminehydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanaminehydrochloride the(S)-1-(4-chloro-3-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid instead of the1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid.

Step 2:(S)-2-(5-((5-(((S)-1-(4-(tert-Butyl)phenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-2-chlorophenoxy)propanoicAcid

The title compound was prepared following the same protocol as describedin Step 6, Example 36, using the (S)-methyl2-(5-((5-(((S)-1-(4-(tert-butyl)phenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-2-chlorophenoxy)propanoateinstead of the (S)-methyl2-(4-((5-((1-(3-cyclopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)acetate.ESI-MS (m/z): 561/562/563 [M+H]⁺.

Example 59:(S)-2-(5-((5-(((S)-1-(3-(tert-Butyl)phenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-2-chlorophenoxy)propanoicAcid

Step 1: (S)-Methyl2-(5-((5-(((S)-1-(3-(tert-butyl)phenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-2-chlorophenoxy)propanoate

The title compound was prepared following the same protocol as describedin Step 5,

Example 36, using the (S)-1-(3-(tert-butyl)phenyl)ethanaminehydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanaminehydrochloride the(S)-1-(4-chloro-3-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid instead of the1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid.

Step 2:(S)-2-(5-((5-(((S)-1-(3-(tert-Butyl)phenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-2-chlorophenoxy)propanoicAcid

The title compound was prepared following the same protocol as describedin Step 6, Example 36, using the (S)-methyl2-(5-((5-(((S)-1-(4-(tert-butyl)phenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-2-chlorophenoxy)propanoateinstead of the (S)-methyl2-(4-((5-((1-(3-cyclopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)acetate.ESI-MS (m/z): 561/562/563 [M+H]⁺.

Example 60:(S)-2-(2-Chloro-5-((5-(((S)-1-(3-isopropoxyphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoicAcid

Step 1: (S)-Methyl2-(5-((5-(((S)-1-(3-isopropoxyphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-2-chlorophenoxy)propanoate

The title compound was prepared following the same protocol as describedin Step 5, Example 36, using the (S)-1-(3-isopropoxyphenyl)ethanaminehydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanaminehydrochloride and(S)-1-(4-chloro-3-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid instead of the1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid.

Step 2:(S)-2-(5-((5-(((S)-1-(3-isopropoxyphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-2-chlorophenoxy)propanoicAcid

The title compound was prepared following the same protocol as describedin Step 6, Example 36, using the (S)-methyl2-(5-((5-(((S)-1-(3-isopropoxyphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-2-chlorophenoxy)propanoateinstead of the (S)-methyl2-(4-((5-((1-(3-cyclopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)acetate.ESI-MS (m/z): 561/562/563 [M+H]⁺.

Example 61:(S)-2-(4-Chloro-3-((5-(((S)-1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoicAcid

Step 1: (S)-Methyl 2-(4-chloro-3-methylphenoxy)propanoate

The title compound was prepared following the same general protocol asdescribed for the synthesis of the (S)-methyl2-(2-chloro-5-methylphenoxy)propanoate (Step 1, Example 55), using the4-chloro-3-methylphenol instead of the 2-chloro-5-methylphenol.

Step 2: (S)-Methyl 2-(3-(bromomethyl)-4-chlorophenoxy)propanoate

The title compound was prepared following the same general protocol asdescribed for the synthesis of the (S)-methyl2-(5-(bromomethyl)-2-chlorophenoxy)propanoate (Step 2, Example 55),using the (S)-methyl 2-(4-chloro-3-methylphenoxy)propanoate instead ofthe (S)-methyl 2-(2-chloro-5-methylphenoxy)propanoate.

Step 3: (S)-Allyl1-(2-chloro-5-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylate

To a solution of the allyl 2,3-dimethyl-1H-indole-5-carboxylate (0.34 g,1.483 mmol) in anhydrous DMF (3 mL) at 0° C. under argon protection wasadded NaH (0.08 g, 2.22 mmol). The mixture was stirred at rt for 30 minand re-cooled to 0° C., and then the (S)-methyl2-(3-(bromomethyl)-4-chlorophenoxy)propanoate (0.55 g, 1.78 mmol) wasadded. The reaction was stirred at rt for another 1 h. The solvent wasremoved to obtain the crude, which was dissolved in EtOAc, then washedwith water and brine and dried over Na₂SO₄. The solvent was removed toobtain the crude. The crude was purified by flash chromatography(AcOEt/Hexane 0˜100%) to obtain the title compound. ESI-MS (m/z): 456[M+1]⁺.

Step 4:(S)-1-(2-Chloro-5-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicAcid

A solution of (S)-allyl1-(2-chloro-5-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylate(0.327 g, 0.72 mmol) and morpholine (0.63 mL, 7.2 mmol) in anhydrous THF(10 mL) was degassed, then Pd(PPh₃)₄ (0.083 g, 0.072 mmol) was addedunder argon protection. The reaction mixture was stirred at rt for 1 h.The solvent was removed and the resulting crude was dissolved in MeOH.The mixture was acidified with 2 N HCl to pH 3. The mixture was filteredand the solid was washed with water. The solid was dried for the nextStep with no further purification. ESI-MS (m/z): 416 [M+1]⁺.

Step 5: (S)-Methyl2-(4-chloro-3-((5-(((S)-1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoate

The(S)-1-(2-chloro-5-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid (71 mg, 0.17 mmol), the (S)-1-(3-isopropylphenyl)ethanaminehydrochloride (53 mg, 0.27 mmol) and HATU (88 mg, 0.23 mmol) weredissolved in DMF (3 mL) and DIEA (0.15 mL). It was stirred for 15 h. Thesolution was filtered and purified by preparative HPLC.

Step 6:(S)-2-(4-Chloro-3-((5-(((S)-1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoicAcid

The (S)-methyl2-(4-chloro-3-((5-(((S)-1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoatewas dissolved in methanol (1.5 mL) and DMSO (˜1 mL), water (0.1 mL) andNaOH (2 N, 0.1 mL) were added dropwise. The reaction was monitored byLC/MS. It was stirred until all the starting material was consumed (˜3h). It was acidified with trifluoroacetic acid, filtered and purified bypreparative HPLC to yield the title compound. ESI-MS (m/z): 547.1[M+H]⁺.

Example 62:(S)-2-(4-Chloro-3-((5-(((S)-1-(3-cyclopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoicAcid

A similar procedure was followed as described in the previous example(Example 61) to yield the title compound. ESI-MS (m/z): 545.1 [M+H]⁺.

Example 63:(S)-2-(3-((5-(((S)-1-(4-Bromophenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-4-chlorophenoxy)propanoicAcid

A similar procedure was followed as described in the previous example(Example 61) to yield the title compound. ESI-MS (m/z): 585.0 [M+H]⁺.

Example 64:(S)-2-(3-((5-(((S)-1-(4-(tert-Butyl)phenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-4-chlorophenoxy)propanoicAcid

Step 1: (S)-Methyl2-(3-((5-(((S)-1-(4-(tert-butyl)phenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-4-chlorophenoxy)propanoate

The title compound was prepared following the same protocol as describedin Step 5, Example 36, using the (S)-1-(4-(tert-butyl)phenyl)ethanaminehydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanaminehydrochloride the(S)-1-(2-chloro-5-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid instead of the1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid.

Step 2:(S)-2-(3-((5-(((S)-1-(4-(tert-Butyl)phenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-4-chlorophenoxy)propanoicAcid

The title compound was prepared following the same protocol as describedin Step 6, Example 36, using the (S)-methyl2-(3-((5-(((S)-1-(4-(tert-butyl)phenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-4-chlorophenoxy)propanoateinstead of the (S)-methyl2-(4-((5-((1-(3-cyclopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)acetate.ESI-MS (m/z): 561/562/563 [M+H]⁺.

Example 65:(S)-2-(3-((5-(((S)-1-(3-(tert-Butyl)phenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-4-chlorophenoxy)propanoicAcid

Step 1: (S)-Methyl2-(3-((5-(((S)-1-(3-(tert-butyl)phenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-4-chlorophenoxy)propanoate

The title compound was prepared following the same protocol as describedin Step 5, Example 36, using the (S)-1-(3-(tert-butyl)phenyl)ethanaminehydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanaminehydrochloride the(S)-1-(2-chloro-5-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid instead of the1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid.

Step 2:(S)-2-(3-((5-(((S)-1-(3-(tert-Butyl)phenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-4-chlorophenoxy)propanoicAcid

The title compound was prepared following the same protocol as describedin Step 6,

Example 36, using the (S)-methyl2-(3-((5-(((S)-1-(4-(tert-butyl)phenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-4-chlorophenoxy)propanoateinstead of the (S)-methyl2-(4-((5-((1-(3-cyclopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)acetate.ESI-MS (m/z): 561/562/563 [M+H]⁺.

Example 66:(S)-2-(4-Chloro-3-((5-(((S)-1-(3-isopropoxyphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoicAcid

Step 1: (S)-Methyl2-(3-((5-(((S)-1-(3-isopropoxyphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-4-chlorophenoxy)propanoate

The title compound was prepared following the same protocol as describedin Step 5, Example 36, using the (S)-1-(3-isopropoxyphenyl)ethanaminehydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanaminehydrochloride the(S)-1-(2-chloro-5-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid instead of the1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid.

Step 2:(S)-2-(4-Chloro-3-((5-(((S)-1-(3-isopropoxyphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoicAcid

The title compound was prepared following the same protocol as describedin Step 6, Example 36, using the (S)-methyl2-(3-((5-(((S)-1-(3-isopropoxyphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-4-chlorophenoxy)propanoateinstead of the (S)-methyl2-(4-((5-((1-(3-cyclopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)acetate.ESI-MS (m/z): 561/562/563 [M+H]⁺.

Example 67:(S)-2-(3-chloro-5-((5-(((S)-1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoicAcid

Step 1: (S)-Methyl 2-(3-chloro-5-methylphenoxy)propanoate

The title compound was prepared following the same protocol as describedin Step 1, Example 42, using the 3-chloro-5-methylphenol instead of them-cresol and the (R)-methyl 2-hydroxypropanoate instead of the(S)-methyl 2-hydroxypropanoate.

Step 2: (S)-Methyl 2-(3-(bromomethyl)-5-chlorophenoxy)propanoate

The title compound was prepared following the same protocol as describedin Step 2, Example 36, using the (S)-methyl2-(3-chloro-5-methylphenoxy)propanoate instead of the methyl2-(p-tolyloxy)acetate.

Step 3: (S)-Allyl1-(3-chloro-5-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylate

The title compound was prepared following the same general protocol asdescribed in Step 3, Example 36, using the (S)-methyl2-(3-(bromomethyl)-5-chlorophenoxy)propanoate instead of the methyl2-(4-(bromomethyl)phenoxy)acetate. ESI-MS (m/z): 456/457/458 [M+H]⁺.

Step 4:(S)-1-(3-Chloro-5-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 4, Example 36, using the (S)-allyl1-(3-chloro-5-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylateinstead of the allyl1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylate.ESI-MS (m/z): 416/417/418 [M+H]⁺.

Step 5: (S)-methyl2-(3-chloro-5-((5-(((S)-1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoate

The title compound was prepared following the same protocol as describedin Step 5, Example 36, using the (S)-1-(3-isopropylphenyl)ethanaminehydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanaminehydrochloride and the(S)-1-(3-chloro-5-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid instead of the1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid.

Step 6:(S)-2-(3-chloro-5-((5-(((S)-1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoicAcid

The title compound was prepared following the same protocol as describedin Step 6, Example 36, using the (S)-methyl2-(3-chloro-5-((5-(((S)-1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoateinstead of the (S)-methyl2-(4-((5-((1-(3-cyclopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)acetate.ESI-MS (m/z): 547/548/549 [M+H]⁺.

Example 68:(S)-2-(2-chloro-3-((5-(((S)-1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoicAcid

Step 1: (S)-Methyl 2-(2-chloro-3-methylphenoxy)propanoate

The title compound was prepared following the same protocol as describedin Step 1, Example 42, using the 2-chloro-3-methylphenol instead of them-cresol and the (R)-methyl 2-hydroxypropanoate instead of the(S)-methyl 2-hydroxypropanoate.

Step 2: (S)-Methyl 2-(3-(bromomethyl)-2-chlorophenoxy)propanoate

The title compound was prepared following the same protocol as describedin Step 2, Example 36, using the (S)-methyl2-(2-chloro-3-methylphenoxy)propanoate instead of the methyl2-(p-tolyloxy)acetate.

Step 3: (S)-Allyl1-(2-chloro-3-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylate

The title compound was prepared following the same general protocol asdescribed in Step 3, Example 36, using the (S)-methyl2-(3-(bromomethyl)-2-chlorophenoxy)propanoate instead of the methyl2-(4-(bromomethyl)phenoxy)acetate. ESI-MS (m/z): 456/457/458 [M+H]⁺.

Step 4:(S)-1-(2-Chloro-3-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 4, Example 36, using the (S)-allyl1-(2-chloro-3-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylateinstead of the allyl1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylate.ESI-MS (m/z): 416/417/418 [M+H]⁺.

Step 5: (S)-methyl2-(2-chloro-3-((5-(((S)-1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoate

The title compound was prepared following the same protocol as describedin Step 5, Example 36, using the (S)-1-(3-isopropylphenyl)ethanaminehydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanaminehydrochloride and the(S)-1-(2-chloro-3-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid instead of the1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid.

Step 6:(S)-2-(2-chloro-3-((5-(((S)-1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoicAcid

The title compound was prepared following the same protocol as describedin Step 6, Example 36, using the (S)-methyl2-(2-chloro-3-((5-(((S)-1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoateinstead of the (S)-methyl2-(4-((5-((1-(3-cyclopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)acetate.ESI-MS (m/z): 547/548/549 [M+H]⁺.

Example 69:(R)-2-(2-Chloro-5-((5-(((S)-1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoicAcid

Step 1: (R)-Methyl 2-(2-chloro-5-methylphenoxy)propanoate

The title compound was prepared following the same protocol as describedin Step 1, Example 42, using the 2-chloro-5-methylphenol instead of them-cresol.

Step 2: (R)-Methyl 2-(5-(bromomethyl)-2-chlorophenoxy)propanoate

The title compound was prepared following the same protocol as describedin Step 2, Example 36, using the (R)-methyl2-(2-chloro-5-methylphenoxy)propanoate instead of the methyl2-(p-tolyloxy)acetate.

Step 3: (R)-Allyl1-(4-chloro-3-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylate

The title compound was prepared following the same general protocol asdescribed in step 3, Example 36, using the (R)-methyl2-(5-(bromomethyl)-2-chlorophenoxy)propanoate instead of the methyl2-(4-(bromomethyl)phenoxy)acetate ESI-MS (m/z): 456 [M+1]⁺.

Step 4:(R)-1-(4-Chloro-3-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 4, Example 36, using the (R)-allyl1-(4-chloro-3-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylateinstead of the allyl1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylate.ESI-MS (m/z): 416 [M+1]⁺.

Step 5: (R)-Methyl2-(2-chloro-5-((5-(((S)-1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoate

The title compound was prepared following the same protocol as describedin Step 5, Example 36, using the (S)-1-(3-isopropylphenyl)ethanaminehydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanaminehydrochloride and the(R)-1-(4-chloro-3-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid instead of the1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid.

Step 6:(R)-2-(2-Chloro-5-((5-(((S)-1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoicAcid

The title compound was prepared following the same protocol as describedin Step 6, Example 36, using the (R)-methyl2-(2-chloro-5-((5-(((S)-1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoateinstead of the (S)-methyl2-(4-((5-((1-(3-cyclopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)acetate.ESI-MS (m/z): 547/548/549 [M+H]⁺.

Example 70:(R)-2-(4-Chloro-3-((5-(((S)-1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoicAcid

Step 1: (R)-Methyl 2-(4-chloro-3-methylphenoxy)propanoate

The title compound was prepared following the same protocol as describedin Step 1, Example 42, using the 4-chloro-3-methylphenol instead of them-cresol.

Step 2: (R)-Methyl 2-(3-(bromomethyl)-4-chlorophenoxy)propanoate

The title compound was prepared following the same protocol as describedin Step 2, Example 36, using the (R)-methyl2-(4-chloro-3-methylphenoxy)propanoate instead of the methyl2-(p-tolyloxy)acetate.

Step 3: (R)-Allyl1-(2-chloro-5-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylate

The title compound was prepared following the same general protocol asdescribed in step 3, Example 36, using the (R)-methyl2-(3-(bromomethyl)-4-chlorophenoxy)propanoate instead of the methyl2-(4-(bromomethyl)phenoxy)acetate ESI-MS (m/z): 456 [M+1]⁺.

Step 4:(R)-1-(2-Chloro-5-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 4, Example 36, using the (R)-allyl1-(2-chloro-5-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylateinstead of the allyl1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylate.ESI-MS (m/z): 416 [M+1]⁺.

Step 5: (R)-Methyl2-(3-chloro-4-((5-(((S)-1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoate

The title compound was prepared following the same protocol as describedin Step 5, Example 36, using the (S)-1-(3-isopropylphenyl)ethanaminehydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanaminehydrochloride and the(R)-1-(2-chloro-5-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid instead of the1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid.

Step 6:(R)-2-(3-Chloro-4-((5-(((S)-1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoicAcid

The title compound was prepared following the same protocol as describedin Step 6, Example 36, using the (R)-methyl2-(3-chloro-4-((5-(((S)-1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoateinstead of the (S)-methyl2-(4-((5-((1-(3-cyclopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)acetate.ESI-MS (m/z): 547/548/549 [M+H]⁺.

Example 71:(R)-2-(3-chloro-5-((5-(((S)-1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoicAcid

Step 1: (R)-Methyl 2-(3-chloro-5-methylphenoxy)propanoate

The title compound was prepared following the same protocol as describedin Step 1, Example 42, using the 3-chloro-5-methylphenol instead of them-cresol.

Step 2: (R)-Methyl 2-(3-(bromomethyl)-5-chlorophenoxy)propanoate

The title compound was prepared following the same protocol as describedin Step 2, Example 36, using the (R)-methyl2-(3-chloro-5-methylphenoxy)propanoate instead of the methyl2-(p-tolyloxy)acetate.

Step 3: (R)-Allyl1-(3-chloro-5-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylate

The title compound was prepared following the same general protocol asdescribed in Step 3, Example 36, using the (R)-methyl2-(3-(bromomethyl)-5-chlorophenoxy)propanoate instead of the methyl2-(4-(bromomethyl)phenoxy)acetate. ESI-MS (m/z): 456/457/458 [M+H]⁺.

Step 4:(R)-1-(3-Chloro-5-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 4, Example 36, using the (R)-allyl1-(3-chloro-5-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylateinstead of the allyl1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylate.ESI-MS (m/z): 416/417/418 [M+H]⁺.

Step 5: (R)-methyl2-(3-chloro-5-((5-(((S)-1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoate

The title compound was prepared following the same protocol as describedin Step 5, Example 36, using the (S)-1-(3-isopropylphenyl)ethanaminehydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanaminehydrochloride and the(R)-1-(3-chloro-5-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid instead of the1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid.

Step 6:(R)-2-(3-chloro-5-((5-(((S)-1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoicAcid

The title compound was prepared following the same protocol as describedin Step 6, Example 36, using the (R)-methyl2-(3-chloro-5-((5-(((S)-1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoateinstead of the (S)-methyl2-(4-((5-((1-(3-cyclopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)acetate.ESI-MS (m/z): 547/548/549 [M+H]⁺.

Example 72:(R)-2-(2-chloro-3-((5-(((S)-1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoicAcid

Step 1: (R)-Methyl 2-(2-chloro-3-methylphenoxy)propanoate

The title compound was prepared following the same protocol as describedin Step 1, Example 42, using the 2-chloro-3-methylphenol instead of them-cresol.

Step 2: (R)-Methyl 2-(3-(bromomethyl)-2-chlorophenoxy)propanoate

The title compound was prepared following the same protocol as describedin Step 2, Example 36, using the (R)-methyl2-(2-chloro-3-methylphenoxy)propanoate instead of the methyl2-(p-tolyloxy)acetate.

Step 3: (R)-Allyl1-(2-chloro-3-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylate

The title compound was prepared following the same general protocol asdescribed in Step 3, Example 36, using the (R)-methyl2-(3-(bromomethyl)-2-chlorophenoxy)propanoate instead of the methyl2-(4-(bromomethyl)phenoxy)acetate. ESI-MS (m/z): 456/457/458 [M+H]⁺.

Step 4:(R)-1-(2-Chloro-3-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 4, Example 36, using the (R)-allyl1-(2-chloro-3-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylateinstead of the allyl1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylate.ESI-MS (m/z): 416/417/418 [M+H]⁺.

Step 5: (R)-methyl2-(2-chloro-3-((5-(((S)-1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoate

The title compound was prepared following the same protocol as describedin Step 5, Example 36, using the (S)-1-(3-isopropylphenyl)ethanaminehydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanaminehydrochloride and the(R)-1-(2-chloro-3-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid instead of the1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid.

Step 6:(R)-2-(2-chloro-3-((5-(((S)-1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoicAcid

The title compound was prepared following the same protocol as describedin Step 6, Example 36, using the (R)-methyl2-(2-chloro-3-((5-(((S)-1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoateinstead of the (S)-methyl2-(4-((5-((1-(3-cyclopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)acetate.ESI-MS (m/z): 547/548/549 [M+H]⁺.

Example 73:(S)-2-(2-chloro-4-((5-(((S)-1-(3-Isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoicAcid

Step 1: (S)-Methyl 2-(2-chloro-4-methylphenoxy)propanoate

The title compound was prepared following the same protocol as describedin Step 1, Example 42, using the 2-chloro-4-methylphenol instead of them-cresol and the (R)-methyl 2-hydroxypropanoate instead of the(S)-methyl 2-hydroxypropanoate.

Step 2: (S)-Methyl 2-(4-(bromomethyl)-2-chlorophenoxy)propanoate

The title compound was prepared following the same protocol as describedin Step 2, Example 36, using the (S)-methyl2-(2-chloro-4-methylphenoxy)propanoate instead of the methyl2-(p-tolyloxy)acetate.

Step 3: (S)-Allyl1-(3-chloro-4-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylate

The title compound was prepared following the same general protocol asdescribed in Step 3, Example 36, using the (S)-methyl2-(4-(bromomethyl)-2-chlorophenoxy)propanoate instead of the methyl2-(4-(bromomethyl)phenoxy)acetate. ESI-MS (m/z): 456/457/458 [M+H]⁺.

Step 4:(S)-1-(3-chloro-4-((1-Methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 4, Example 36, using the (S)-allyl1-(3-chloro-4-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylateinstead of the allyl1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylate.ESI-MS (m/z): 416/417/418 [M+H]⁺.

Step 5: (S)-Methyl2-(2-chloro-4-((5-(((S)-1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoate

The title compound was prepared following the same protocol as describedin Step 5, Example 36, using the (S)-1-(3-isopropylphenyl)ethanaminehydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanaminehydrochloride and the(S)-1-(3-chloro-4-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid instead of the1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid.

Step 6:(S)-2-(2-chloro-4-((5-(((S)-1-(3-Isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoicAcid

The title compound was prepared following the same protocol as describedin Step 6, Example 36, using the (S)-methyl2-(2-chloro-4-((5-(((S)-1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoateinstead of the (S)-methyl2-(4-((5-((1-(3-cyclopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)acetate.ESI-MS (m/z): 547/548/549 [MH]⁺.

Example 74:(S)-2-(3-chloro-4-((5-(((S)-1-(3-Isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoicAcid

Step 1: (S)-Methyl 2-(3-chloro-4-methylphenoxy)propanoate

The title compound was prepared following the same protocol as describedin Step 1, Example 42, using the 3-chloro-4-methylphenol instead of them-cresol and the (R)-methyl 2-hydroxypropanoate instead of the(S)-methyl 2-hydroxypropanoate.

Step 2: (S)-Methyl 2-(4-(bromomethyl)-3-chlorophenoxy)propanoate

The title compound was prepared following the same protocol as describedin Step 2, Example 36, using the (S)-methyl2-(3-chloro-4-methylphenoxy)propanoate instead of the methyl2-(p-tolyloxy)acetate.

Step 3: (S)-Allyl1-(2-chloro-4-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylate

The title compound was prepared following the same general protocol asdescribed in Step 3, Example 36, using the (S)-methyl2-(4-(bromomethyl)-3-chlorophenoxy)propanoate instead of the methyl2-(4-(bromomethyl)phenoxy)acetate. ESI-MS (m/z): 456/457/458 [M+H]⁺.

Step 4:(S)-1-(2-chloro-4-((1-Methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 4, Example 36, using the (S)-allyl1-(2-chloro-4-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylateinstead of the allyl1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylate.ESI-MS (m/z): 416/417/418 [M+H]⁺.

Step 5: (S)-Methyl2-(3-chloro-4-((5-(((S)-1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoate

The title compound was prepared following the same protocol as describedin Step 5, Example 36, using the (S)-1-(3-isopropylphenyl)ethanaminehydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanaminehydrochloride and the(S)-1-(2-chloro-4-(1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid instead of the1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid.

Step 6:(S)-2-(3-chloro-4-((5-(((S)-1-(3-Isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoicAcid

The title compound was prepared following the same protocol as describedin Step 6, Example 36, using the (S)-methyl2-(3-chloro-4-((5-(((S)-1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoateinstead of the (S)-methyl2-(4-((5-((1-(3-cyclopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)acetate.ESI-MS (m/z): 547/548/549 [MH]⁺.

Example 75:(R)-2-(2-chloro-4-((5-(((S)-1-(3-Isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoicAcid

Step 1: (R)-Methyl 2-(2-chloro-4-methylphenoxy)propanoate

The title compound was prepared following the same protocol as describedin Step 1, Example 42, using the 2-chloro-4-methylphenol instead of them-cresol.

Step 2: (R)-Methyl 2-(4-(bromomethyl)-2-chlorophenoxy)propanoate

The title compound was prepared following the same protocol as describedin Step 2, Example 36, using the (R)-methyl2-(2-chloro-4-methylphenoxy)propanoate instead of the methyl2-(p-tolyloxy)acetate.

Step 3: (R)-Allyl1-(3-chloro-4-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylate

The title compound was prepared following the same general protocol asdescribed in Step 3, Example 36, using the (R)-methyl2-(4-(bromomethyl)-2-chlorophenoxy)propanoate instead of the methyl2-(4-(bromomethyl)phenoxy)acetate. ESI-MS (m/z): 456/457/458 [M+H]⁺.

Step 4:(R)-1-(3-chloro-4-((1-Methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 4, Example 36, using the (R)-allyl1-(3-chloro-4-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylateinstead of the allyl1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylate.ESI-MS (m/z): 416/417/418 [M+H]⁺.

Step 5: (R)-Methyl2-(2-chloro-4-((5-(((S)-1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoate

The title compound was prepared following the same protocol as describedin Step 5, Example 36, using the (S)-1-(3-isopropylphenyl)ethanaminehydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanaminehydrochloride and the(R)-1-(3-chloro-4-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid instead of the1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid.

Step 6:(R)-2-(2-chloro-4-((5-(((S)-1-(3-Isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoicAcid

The title compound was prepared following the same protocol as describedin Step 6, Example 36, using the (R)-methyl2-(2-chloro-4-((5-(((S)-1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoateinstead of the (S)-methyl2-(4-((5-((1-(3-cyclopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)acetate.ESI-MS (m/z): 547/548/549 [MH]⁺

Example 76:(R)-2-(3-chloro-4-((5-(((S)-1-(3-Isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoicAcid

Step 1: (R)-Methyl 2-(3-chloro-4-methylphenoxy)propanoate

The title compound was prepared following the same protocol as describedin Step 1, Example 42, using the 3-chloro-4-methylphenol instead of them-cresol.

Step 2: (R)-Methyl 2-(4-(bromomethyl)-3-chlorophenoxy)propanoate

The title compound was prepared following the same protocol as describedin Step 2, Example 36, using the (R)-methyl2-(3-chloro-4-methylphenoxy)propanoate instead of the methyl2-(p-tolyloxy)acetate.

Step 3: (R)-Allyl1-(2-chloro-4-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylate

The title compound was prepared following the same general protocol asdescribed in Step 3, Example 36, using the (R)-methyl2-(4-(bromomethyl)-3-chlorophenoxy)propanoate instead of the methyl2-(4-(bromomethyl)phenoxy)acetate. ESI-MS (m/z): 456/457/458 [M+H]⁺.

Step 4:(R)-1-(2-chloro-4-((1-Methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 4, Example 36, using the (R)-allyl1-(2-chloro-4-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylateinstead of the allyl1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylate.ESI-MS (m/z): 416/417/418 [M+H]⁺.

Step 5: (R)-Methyl2-(3-chloro-4-((5-(((S)-1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoate

The title compound was prepared following the same protocol as describedin Step 5, Example 36, using the (S)-1-(3-isopropylphenyl)ethanaminehydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanaminehydrochloride and the(R)-1-(2-chloro-4-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid instead of the1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid.

Step 6:(R)-2-(3-chloro-4-((5-(((S)-1-(3-Isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoicAcid

The title compound was prepared following the same protocol as describedin Step 6, Example 36, using the (R)-methyl2-(3-chloro-4-((5-(((S)-1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoateinstead of the (S)-methyl2-(4-((5-((1-(3-cyclopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)acetate.ESI-MS (m/z): 547/548/549 [MH]⁺.

Example 77:(S)-2-(3-((5-(((S)-1-(3-Isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)butanoicAcid

Step 1: (S)-Methyl 2-(m-tolyloxy)butanoate

The title compound was prepared following the same protocol as describedin Step 1, Example 42, using the (R)-methyl 2-hydroxybutanoate insteadof the (S)-methyl 2-hydroxypropanoate.

Step 2: (S)-Methyl 2-(3-(bromomethyl)phenoxy)butanoate

The title compound was prepared following the same protocol as describedin Step 2, Example 36, using the (S)-methyl 2-(m-tolyloxy)butanoateinstead of the methyl 2-(p-tolyloxy)acetate.

Step 3: (S)-Allyl1-(3-((1-methoxy-1-oxobutan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylate

The title compound was prepared following the same general protocol asdescribed in Step 3, Example 36, using the (S)-methyl2-(3-(bromomethyl)phenoxy)butanoate instead of the methyl2-(4-(bromomethyl)phenoxy)acetate. ESI-MS (m/z): 436 [M+H]⁺.

Step 4:(S)-1-((3-((1-Methoxy-1-oxobutan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 4, Example 36, using the (S)-allyl1-(3-((1-methoxy-1-oxobutan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylateinstead of the allyl1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylate.ESI-MS (m/z): 382 [M+H]⁺.

Step 5: (S)-Methyl2-(3-((5-(((S)-1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)butanoate

The title compound was prepared following the same protocol as describedin Step 5, Example 36, using the (S)-1-(3-isopropylphenyl)ethanaminehydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanaminehydrochloride and the(S)-1-((3-((1-methoxy-1-oxobutan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid instead of the1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid.

Step 6:(S)-2-(3-((5-(((S)-1-(3-Isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)butanoicAcid

The title compound was prepared following the same protocol as describedin Step 6, Example 36, using the (S)-methyl2-(3-((5-(((S)-1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)butanoateinstead of the (S)-methyl2-(4-((5-((1-(3-cyclopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)acetate.ESI-MS (m/z): 527 [M+H]⁺.

Example 78:(R)-2-(3-((5-(((S)-1-(3-Isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)butanoicAcid

Step 1: (R)-Methyl 2-(m-tolyloxy)butanoate

The title compound was prepared following the same protocol as describedin Step 1, Example 42, using the (S)-methyl 2-hydroxybutanoate insteadof the (S)-methyl 2-hydroxypropanoate.

Step 2: (R)-Methyl 2-(3-(bromomethyl)phenoxy)butanoate

The title compound was prepared following the same protocol as describedin Step 2, Example 36, using the (R)-methyl 2-(m-tolyloxy)butanoateinstead of the methyl 2-(p-tolyloxy)acetate.

Step 3: (R)-Allyl1-(3-((1-methoxy-1-oxobutan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylate

The title compound was prepared following the same general protocol asdescribed in Step 3, Example 36, using the (R)-methyl2-(3-(bromomethyl)phenoxy)butanoate instead of the methyl2-(4-(bromomethyl)phenoxy)acetate. ESI-MS (m/z): 436 [M+H]⁺.

Step 4:(R)-1-(3-((1-Methoxy-1-oxobutan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 4, Example 36, using the (R)-allyl1-(3-((1-methoxy-1-oxobutan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylateinstead of the allyl1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylate.ESI-MS (m/z): 382 [M+H]⁺.

Step 5: (R)-Methyl2-(3-((5-(((S)-1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)butanoate

The title compound was prepared following the same protocol as describedin Step 5, Example 36, using the (S)-1-(3-isopropylphenyl)ethanaminehydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanaminehydrochloride and the(R)-1-(3-((1-methoxy-1-oxobutan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid instead of the1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid.

Step 6:(R)-2-(3-((5-(((S)-1-(3-Isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)butanoicAcid

The title compound was prepared following the same protocol as describedin Step 6, Example 36, using the (R)-methyl2-(3-((5-(((S)-1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)butanoateinstead of the (S)-methyl2-(4-((5-((1-(3-cyclopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)acetate.ESI-MS (m/z): 527 [M+H]⁺.

Example 79:(S)-2-(3-((5-(((S)-1-(3-Isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)-3-methylbutanoicAcid

Step 1: (S)-Methyl 3-methyl-2-(m-tolyloxy)butanoate

The title compound was prepared following the same protocol as describedin Step 1, Example 42, using the (R)-methyl 2-hydroxy-3-methylbutanoateinstead of the (S)-methyl 2-hydroxypropanoate.

Step 2: (S)-Methyl 2-(3-(bromomethyl)phenoxy)-3-methylbutanoate

The title compound was prepared following the same protocol as describedin Step 2, Example 36, using the (S)-methyl3-methyl-2-(m-tolyloxy)butanoate instead of the methyl2-(p-tolyloxy)acetate.

Step 3: (S)-Allyl1-(3-((1-methoxy-3-methyl-1-oxobutan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylate

The title compound was prepared following the same general protocol asdescribed in Step 3, Example 36, using the (S)-methyl2-(3-(bromomethyl)phenoxy)-3-methylbutanoate instead of the methyl2-(4-(bromomethyl)phenoxy)acetate. ESI-MS (m/z): 450 [M+H]⁺.

Step 4:(S)-1-(3-((1-Methoxy-3-methyl-1-oxobutan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 4, Example 36, using the (S)-allyl1-(3-((1-methoxy-3-methyl-1-oxobutan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylateinstead of the allyl1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylate.ESI-MS (m/z): 396 [M+H]⁺.

Step 5: (S)-Methyl2-(3-((5-(((S)-1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)-3-methylbutanoate

The title compound was prepared following the same protocol as describedin Step 5, Example 36, using the (S)-1-(3-isopropylphenyl)ethanaminehydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanaminehydrochloride and the(S)-1-(3-((1-methoxy-3-methyl-1-oxobutan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid instead of the1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid.

Step 6:(S)-2-(3-((5-(((S)-1-((3-Isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)-3-methylbutanoicAcid

The title compound was prepared following the same protocol as describedin Step 6, Example 36, using the (S)-methyl2-(3-((5-(((S)-1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)-3-methylbutanoateinstead of the (S)-methyl2-(4-((5-((1-(3-cyclopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)acetate.ESI-MS (m/z): 541 [M+H]⁺.

Example 80:(R)-2-(3-((5-(((S)-1-(3-Isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)-3-methylbutanoicAcid

Step 1: (R)-Methyl 3-methyl-2-(m-tolyloxy)butanoate

The title compound was prepared following the same protocol as describedin Step 1, Example 42, using the (S)-methyl 2-hydroxy-3-methylbutanoateinstead of the (S)-methyl 2-hydroxypropanoate.

Step 2: (R)-Methyl 2-(3-(bromomethyl)phenoxy)3-methylbutanoate

The title compound was prepared following the same protocol as describedin Step 2, Example 36, using the (R)-methyl3-methyl-2-(m-tolyloxy)butanoate instead of the methyl2-(p-tolyloxy)acetate.

Step 3: (R)-Allyl1-(3-((1-methoxy-3-methyl-1-oxobutan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylate

The title compound was prepared following the same general protocol asdescribed in Step 3, Example 36, using the (R)-methyl2-(3-(bromomethyl)phenoxy)-3-methylbutanoate instead of the methyl2-(4-(bromomethyl)phenoxy)acetate. ESI-MS (m/z): 450 [M+H]⁺.

Step 4:(R)-1-(3-((1-Methoxy-3-methyl-1-oxobutan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 4, Example 36, using the (R)-allyl1-(34(1-methoxy-3-methyl-1-oxobutan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylateinstead of the allyl1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylate.ESI-MS (m/z): 396 [M+H]⁺.

Step 5: (R)-Methyl2-(3-((5-(((S)-1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)-3-methylbutanoate

The title compound was prepared following the same protocol as describedin Step 5, Example 36, using the (S)-1-(3-isopropylphenyl)ethanaminehydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanaminehydrochloride and the(R)-1-(3-((1-methoxy-3-methyl-1-oxobutan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid instead of the1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid.

Step 6:(R)-2-(3-((5-(((S)-1-(3-Isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)-3-methylbutanoicAcid

The title compound was prepared following the same protocol as describedin Step 6, Example 36, using the (R)-methyl2-(3-((5-(((S)-1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)-3-methylbutanoateinstead of the (S)-methyl2-(4-((5-((1-(3-cyclopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)acetate.ESI-MS (m/z): 541 [M+H]⁺

Example 81:(S)-2-(2-Chloro-5-((5-(((S)-1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)butanoicAcid

Step 1: (S)-Methyl 2-(2-chloro-5-methylphenoxy)butanoate

The title compound was prepared following the same protocol as describedin Step 1, Example 42, using the (R)-methyl 2-hydroxybutanoate insteadof the (S)-methyl 2-hydroxypropanoate and the 2-chloro-5-methylphenolinstead of the m-cresol.

Step 2: (S)-Methyl 2-(5-(bromomethyl)-2-chlorophenoxy)butanoate

The title compound was prepared following the same protocol as describedin Step 2, Example 36, using the (S)-methyl2-(2-chloro-5-methylphenoxy)butanoate instead of the methyl2-(p-tolyloxy)acetate.

Step 3: (S)-Allyl1-(4-chloro-3-((1-methoxy-1-oxobutan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylate

The title compound was prepared following the same general protocol asdescribed in Step 3, Example 36, using the (S)-methyl2-(5-(bromomethyl)-2-chlorophenoxy)butanoate instead of the methyl2-(4-(bromomethyl)phenoxy)acetate. ESI-MS (m/z): 470/471/472 [M+H]⁺.

Step 4:(S)-1-(4-Chloro-3-((1-methoxy-1-oxobutan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 4, Example 36, using the (S)-allyl1-(4-chloro-3-((1-methoxy-1-oxobutan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylateinstead of the allyl1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylate.ESI-MS (m/z): 430/431/432 [M+H]⁺.

Step 5: (S)-Methyl2-(2-chloro-5-((5-(((S)-1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)butanoate

The title compound was prepared following the same protocol as describedin Step 5, Example 36, using the (S)-1-(3-isopropylphenyl)ethanaminehydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanaminehydrochloride and the(S)-1-(4-chloro-3-((1-methoxy-1-oxobutan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid instead of the1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid.

Step 6:(S)-2-(2-Chloro-5-((5-(((S)-1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)butanoicAcid

The title compound was prepared following the same protocol as describedin Step 6, Example 36, using the (S)-methyl2-(2-chloro-5-((5-(((S)-1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)butanoateinstead of the (S)-methyl2-(4-((5-((1-(3-cyclopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)acetate.ESI-MS (m/z): 561/562/563 [M+H]⁺.

Example 82:(S)-2-(4-Chloro-3-((5-(((S)-1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)butanoicAcid

Step 1: (S)-Methyl 2-(4-chloro-3-methylphenoxy)butanoate

The title compound was prepared following the same protocol as describedin Step 1, Example 42, using the (R)-methyl 2-hydroxybutanoate insteadof the (S)-methyl 2-hydroxypropanoate and the 4-chloro-3-methylphenolinstead of the m-cresol.

Step 2: (S)-Methyl 2-(3-(bromomethyl)-4-chlorophenoxy)butanoate

The title compound was prepared following the same protocol as describedin Step 2, Example 36, using the (S)-methyl2-(4-chloro-3-methylphenoxy)butanoate instead of the methyl2-(p-tolyloxy)acetate.

Step 3: (S)-Allyl1-(2-chloro-5-((1-methoxy-1-oxobutan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylate

The title compound was prepared following the same general protocol asdescribed in Step 3, Example 36, using the (S)-methyl2-(3-(bromomethyl)-4-chlorophenoxy)butanoate instead of the methyl2-(4-(bromomethyl)phenoxy)acetate. ESI-MS (m/z): 470/471/472 [M+H]⁺.

Step 4:(S)-1-(2-Chloro-5-((1-methoxy-1-oxobutan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 4, Example 36, using the (S)-allyl1-(2-chloro-5-((1-methoxy-1-oxobutan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylateinstead of the allyl1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylate.ESI-MS (m/z): 430/431/432 [M+H]⁺.

Step 5: (S)-Methyl2-(4-chloro-3-((5-(((S)-1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)butanoate

The title compound was prepared following the same protocol as describedin Step 5, Example 36, using the (S)-1-(3-isopropylphenyl)ethanaminehydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanaminehydrochloride and the(S)-1-(2-chloro-5-((1-methoxy-1-oxobutan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid instead of the1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid.

Step 6:(S)-2-(4-Chloro-3-((5-(((S)-1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)butanoicAcid

The title compound was prepared following the same protocol as describedin Step 6, Example 36, using the (S)-methyl2-(4-chloro-3-((5-(((S)-1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)butanoateinstead of the (S)-methyl2-(4-((5-((1-(3-cyclopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)acetate.ESI-MS (m/z): 561/562/563 [M+H]⁺.

Example 83:(R)-2-(2-Chloro-5-((5-(((S)-1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)butanoicAcid

Step 1: (R)-Methyl 2-(2-chloro-5-methylphenoxy)butanoate

The title compound was prepared following the same protocol as describedin Step 1, Example 42, using the (S)-methyl 2-hydroxybutanoate insteadof the (S)-methyl 2-hydroxypropanoate and the 2-chloro-5-methylphenolinstead of the m-cresol.

Step 2: (R)-Methyl 2-(5-(bromomethyl)-2-chlorophenoxy)butanoate

The title compound was prepared following the same protocol as describedin Step 2, Example 36, using the (R)-methyl2-(2-chloro-5-methylphenoxy)butanoate instead of the methyl2-(p-tolyloxy)acetate.

Step 3: (R)-Allyl1-(4-chloro-3-((1-methoxy-1-oxobutan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylate

The title compound was prepared following the same general protocol asdescribed in Step 3, Example 36, using the (R)-methyl2-(5-(bromomethyl)-2-chlorophenoxy)butanoate instead of the methyl2-(4-(bromomethyl)phenoxy)acetate. ESI-MS (m/z): 470/471/472 [M+H]⁺.

Step 4:(R)-1-(4-Chloro-3-((1-methoxy-1-oxobutan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 4, Example 36, using the (R)-allyl1-(4-chloro-3-((1-methoxy-1-oxobutan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylateinstead of the allyl1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylate.ESI-MS (m/z): 430/431/432 [M+H]⁺.

Step 5: (R)-Methyl2-(2-chloro-5-((5-(((S)-1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)butanoate

The title compound was prepared following the same protocol as describedin Step 5, Example 36, using the (S)-1-(3-isopropylphenyl)ethanaminehydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanaminehydrochloride and the(R)-1-(4-chloro-3-((1-methoxy-1-oxobutan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid instead of the1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid.

Step 6:(R)-2-(2-chloro-5-((5-(((S)-1-(3-Isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)butanoicAcid

The title compound was prepared following the same protocol as describedin Step 6, Example 36, using the (R)-methyl2-(2-chloro-5-((5-(((S)-1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)butanoateinstead of the (S)-methyl2-(4-((5-((1-(3-cyclopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)acetate.ESI-MS (m/z): 561/562/563 [M+H]⁺.

Example 84:(R)-2-(4-Chloro-3-((5-(((S)-1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)butanoicAcid

Step 1: (R)-Methyl 2-(4-chloro-3-methylphenoxy)butanoate

The title compound was prepared following the same protocol as describedin Step 1, Example 42, using the (S)-methyl 2-hydroxybutanoate insteadof the (S)-methyl 2-hydroxypropanoate and the 4-chloro-3-methylphenolinstead of the m-cresol.

Step 2: (R)-Methyl 2-(3-(bromomethyl)-4-chlorophenoxy)butanoate

The title compound was prepared following the same protocol as describedin Step 2, Example 36, using the (R)-methyl2-(4-chloro-3-methylphenoxy)butanoate instead of the methyl2-(p-tolyloxy)acetate.

Step 3: (R)-Allyl1-(2-chloro-5-((1-methoxy-1-oxobutan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylate

The title compound was prepared following the same general protocol asdescribed in Step 3, Example 36, using the (R)-methyl2-(3-(bromomethyl)-4-chlorophenoxy)butanoate instead of the methyl2-(4-(bromomethyl)phenoxy)acetate. ESI-MS (m/z): 470/471/472 [M+H]⁺.

Step 4:(R)-1-(2-Chloro-5-((1-methoxy-1-oxobutan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 4, Example 36, using the (R)-allyl1-(2-chloro-5-((1-methoxy-1-oxobutan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylateinstead of the allyl1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylate.ESI-MS (m/z): 430/431/432 [M+H]⁺.

Step 5: (R)-Methyl2-(4-chloro-3-((5-(((S)-1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)butanoate

The title compound was prepared following the same protocol as describedin Step 5, Example 36, using the (S)-1-(3-isopropylphenyl)ethanaminehydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanaminehydrochloride and the(R)-1-(2-chloro-5-((1-methoxy-1-oxobutan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid instead of the1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid.

Step 6:(R)-2-(4-Chloro-3-((5-(((S)-1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)butanoicAcid

The title compound was prepared following the same protocol as describedin Step 6, Example 36, using the (R)-methyl2-(4-chloro-3-((5-(((S)-1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)butanoateinstead of the (S)-methyl2-(4-((5-((1-(3-cyclopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)acetate.ESI-MS (m/z): 561/562/563 [M+H]⁺.

Example 85:(S)-2-(2-Chloro-5-((5-(((S)-1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)-3-methylbutanoicAcid

Step 1: (S)-Methyl 2-(2-chloro-5-methylphenoxy)-3-methylbutanoate

The title compound was prepared following the same protocol as describedin Step 1, Example 42, using the (R)-methyl 2-hydroxy-3-methylbutanoateinstead of the (S)-methyl 2-hydroxypropanoate and the2-chloro-5-methylphenol instead of the m-cresol.

Step 2: (S)-Methyl 2-(5-(bromomethyl)-2-chlorophenoxy)-3-methylbutanoate

The title compound was prepared following the same protocol as describedin Step 2, Example 36, using the (S)-methyl2-(2-chloro-5-methylphenoxy)-3-methylbutanoate instead of the methyl2-(p-tolyloxy)acetate.

Step 3: (S)-Allyl1-(4-chloro-3-((1-methoxy-3-methyl-1-oxobutan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylate

The title compound was prepared following the same general protocol asdescribed in Step 3, Example 36, using the (S)-methyl2-(5-(bromomethyl)-2-chlorophenoxy)-3-methylbutanoate instead of themethyl 2-(4-(bromomethyl)phenoxy)acetate. ESI-MS (m/z): 470/471/472[M+H]⁺.

Step 4:(S)-1-(4-Chloro-3-((1-methoxy-3-methyl-1-oxobutan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 4, Example 36, using the (S)-allyl1-(4-chloro-3-((1-methoxy-3-methyl-1-oxobutan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylateinstead of the allyl1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylate.ESI-MS (m/z): 430/431/432 [M+H]⁺.

Step 5: (S)-Methyl2-(2-chloro-5-((5-(((S)-1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)-3-methylbutanoate

The title compound was prepared following the same protocol as describedin Step 5, Example 36, using the (S)-1-(3-isopropylphenyl)ethanaminehydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanaminehydrochloride and the(S)-1-(4-chloro-34(1-methoxy-3-methyl-1-oxobutan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid instead of the1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid.

Step 6:(S)-2-(2-Chloro-5-((5-(((S)-1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)-3-methylbutanoicAcid

The title compound was prepared following the same protocol as describedin Step 6, Example 36, using the (S)-methyl2-(2-chloro-5-((5-(((S)-1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)-3-methylbutanoateinstead of the (S)-methyl2-(4-(((5-((1-(3-cyclopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)acetate.ESI-MS (m/z): 561/562/563 [M+H]⁺.

Example 86:(S)-2-(4-Chloro-3-((5-(((S)-1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)-3-methylbutanoicAcid

Step 1: (S)-Methyl 2-(4-chloro-3-methylphenoxy)-3-methylbutanoate

The title compound was prepared following the same protocol as describedin Step 1, Example 42, using the (R)-methyl 2-hydroxy-3-methylbutanoateinstead of the (S)-methyl 2-hydroxypropanoate and the4-chloro-3-methylphenol instead of the m-cresol.

Step 2: (S)-Methyl 2-(3-(bromomethyl)-4-chlorophenoxy)-3-methylbutanoate

The title compound was prepared following the same protocol as describedin Step 2, Example 36, using the (S)-methyl2-(4-chloro-3-methylphenoxy)-3-methylbutanoate instead of the methyl2-(p-tolyloxy)acetate.

Step 3: (S)-Allyl1-(2-chloro-5-((1-methoxy-3-methyl-1-oxobutan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylate

The title compound was prepared following the same general protocol asdescribed in Step 3, Example 36, using the (S)-methyl2-(3-(bromomethyl)-4-chlorophenoxy)-3-methylbutanoate instead of themethyl 2-(4-(bromomethyl)phenoxy)acetate. ESI-MS (m/z): 470/471/472[M+H]⁺.

Step 4:(S)-1-(2-Chloro-5-((1-methoxy-3-methyl-1-oxobutan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 4, Example 36, using the (S)-allyl1-(2-chloro-5-((1-methoxy-3-methyl-1-oxobutan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylateinstead of the allyl1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylate.ESI-MS (m/z): 430/431/432 [M+H]⁺.

Step 5: (S)-Methyl2-(4-chloro-3-((5-(((S)-1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)-3-methylbutanoate

The title compound was prepared following the same protocol as describedin Step 5, Example 36, using the (S)-1-(3-isopropylphenyl)ethanaminehydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanaminehydrochloride and the(S)-1-(2-chloro-5-((1-methoxy-3-methyl-1-oxobutan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid instead of the1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid.

Step 6:(S)-2-(4-Chloro-3-((5-(((S)-1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)-3-methylbutanoicAcid

The title compound was prepared following the same protocol as describedin Step 6, Example 36, using the (S)-methyl2-(4-chloro-3-((5-(((S)-1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)-3-methylbutanoateinstead of the (S)-methyl2-(4-((5-((1-(3-cyclopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)acetate.ESI-MS (m/z): 561/562/563 [M+H]⁺.

Example 87:(R)-2-(2-Chloro-5-((5-(((S)-1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)-3-methylbutanoicAcid

Step 1: (R)-Methyl 2-(2-chloro-5-methylphenoxy)-3-methylbutanoate

The title compound was prepared following the same protocol as describedin Step 1, Example 42, using the (S)-methyl 2-hydroxy-3-methylbutanoateinstead of the (S)-methyl 2-hydroxypropanoate and the2-chloro-5-methylphenol instead of the m-cresol.

Step 2: (R)-Methyl 2-(5-(bromomethyl)-2-chlorophenoxy)-3-methylbutanoate

The title compound was prepared following the same protocol as describedin Step 2, Example 36, using the (R)-methyl2-(2-chloro-5-methylphenoxy)-3-methylbutanoate instead of the methyl2-(p-tolyloxy)acetate.

Step 3: (R)-Allyl1-(4-chloro-3-((1-methoxy-3-methyl-1-oxobutan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylate

The title compound was prepared following the same general protocol asdescribed in Step 3, Example 36, using the (R)-methyl2-(5-(bromomethyl)-2-chlorophenoxy)-3-methylbutanoate instead of themethyl 2-(4-(bromomethyl)phenoxy)acetate. ESI-MS (m/z): 470/471/472[M+H]⁺.

Step 4:(R)-1-(4-Chloro-3-((1-methoxy-3-methyl-1-oxobutan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 4, Example 36, using the (R)-allyl1-(4-chloro-3-((1-methoxy-3-methyl-1-oxobutan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylateinstead of the allyl1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylate.ESI-MS (m/z): 430/431/432 [M+H]⁺.

Step 5: (R)-Methyl2-(2-chloro-5-((5-(((S)-1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)-3-methylbutanoate

The title compound was prepared following the same protocol as describedin Step 5, Example 36, using the (S)-1-(3-isopropylphenyl)ethanaminehydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanaminehydrochloride and the(R)-1-(4-chloro-3-((1-methoxy-3-methyl-1-oxobutan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid instead of the1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid.

Step 6:(R)-2-(2-Chloro-5-((5-(((S)-1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)-3-methylbutanoicAcid

The title compound was prepared following the same protocol as describedin Step 6, Example 36, using the (R)-methyl2-(2-chloro-5-((5-(((S)-1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)-3-methylbutanoateinstead of the (S)-methyl2-(4-(((5-((1-(3-cyclopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)acetate.ESI-MS (m/z): 561/562/563 [M+H]⁺.

Example 88:(R)-2-(4-Chloro-3-((5-(((S)-1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)-3-methylbutanoicAcid

Step 1: (R)-Methyl 2-(4-chloro-3-methylphenoxy)-3-methylbutanoate

The title compound was prepared following the same protocol as describedin Step 1, Example 42, using the (S)-methyl 2-hydroxybutanoate insteadof the (S)-methyl 2-hydroxy-3-methylpropanoate and the4-chloro-3-methylphenol instead of the m-cresol.

Step 2: (R)-Methyl 2-(3-(bromomethyl)-4-chlorophenoxy)-3-methylbutanoate

The title compound was prepared following the same protocol as describedin Step 2, Example 36, using the (R)-methyl2-(4-chloro-3-methylphenoxy)-3-methylbutanoate instead of the methyl2-(p-tolyloxy)acetate.

Step 3: (R)-Allyl1-(2-chloro-5-((1-methoxy-3-methyl-1-oxobutan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylate

The title compound was prepared following the same general protocol asdescribed in Step 3, Example 36, using the (R)-methyl2-(3-(bromomethyl)-4-chlorophenoxy)-3-methylbutanoate instead of themethyl 2-(4-(bromomethyl)phenoxy)acetate. ESI-MS (m/z): 470/471/472[M+H]⁺.

Step 4:(R)-1-(2-Chloro-5-((1-methoxy-3-methyl-1-oxobutan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 4, Example 36, using the (R)-allyl1-(2-chloro-5-((1-methoxy-3-methyl-1-oxobutan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylateinstead of the allyl1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylate.ESI-MS (m/z): 430/431/432 [M+H]⁺.

Step 5: (R)-Methyl2-(4-chloro-3-((5-(((S)-1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)-3-methylbutanoate

The title compound was prepared following the same protocol as describedin Step 5, Example 36, using the (S)-1-(3-isopropylphenyl)ethanaminehydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanaminehydrochloride and the(R)-1-(2-chloro-5-((1-methoxy-3-methyl-1-oxobutan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid instead of the1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid.

Step 6:(R)-2-(4-Chloro-3-((5-(((S)-1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)-3-methylbutanoicAcid

The title compound was prepared following the same protocol as describedin Step 6, Example 36, using the (R)-methyl2-(4-chloro-3-((5-(((S)-1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)-3-methylbutanoateinstead of the (S)-methyl2-(4-((5-((1-(3-cyclopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)acetate.ESI-MS (m/z): 561/562/563 [M+H]⁺.

Example 89:1-(4-((2,3-dimethyl-5-((1-phenylpropyl)carbamoyl)-1H-indol-1-yl)methyl)phenyl)cyclopropanecarboxylicAcid

The title compound was prepared following the same protocol as describedin Step 5 and 8, Example 35, using the 1-phenylpropanamine instead ofthe (S)-1-(3-bromophenyl)ethanamine. ESI-MS (m/z): 481 [MH]⁺.

Example 90:(S)-1-(4-((5-((1-(4-bromophenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenyl)cyclopropanecarboxylicAcid

The title compound was prepared following the same protocol as describedin Step 5 and 8, Example 35, using the (S)-1-(4-bromophenyl)ethanamineinstead of the (S)-1-(3-bromophenyl)ethanamine. ESI-MS (m/z): 545/547[MH]⁺.

Example 91:(S)-1-(4-((5-((1-(4-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenyl)cyclopropanecarboxylicAcid

The title compound was prepared following the same protocol as describedin Step 5-8, Example 35, using the (S)-1-(4-bromophenyl)ethanamineinstead of the (S)-1-(3-bromophenyl)ethanamine. ESI-MS (m/z): 509 [MH]⁺.

Example 92:(S)-2-(3-chloro-5-((5-(((S)-1-(3-cyclopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoicAcid

The title compound was prepared following the same protocol as describedin Step 5-6, Example 67, using the (S)-1-(3-cyclopropylphenyl)ethanaminehydrochloride instead of the (S)-1-(3-isopropylphenyl)ethanaminehydrochloride. ESI-MS (m/z): 545/546/547 [MH]⁺.

Example 93:(S)-2-(3-((5-(((S)-1-(4-(tert-butyl)phenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-5-chlorophenoxy)propanoicAcid

The title compound was prepared following the same protocol as describedin Step 5-6, Example 67, using the (S)-1-(4-tert-butylphenyl)ethanaminehydrochloride instead of the (S)-1-(3-isopropylphenyl)ethanaminehydrochloride. ESI-MS (m/z): 561/562/563 [MH]⁺.

Example 94:(S)-2-(2-chloro-4-((5-(((S)-1-(3-cyclopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoicAcid

The title compound was prepared following the same protocol as describedin Step 5-6, Example 73, using the (S)-1-(3-cyclopropylphenyl)ethanaminehydrochloride instead of the (S)-1-(3-isopropylphenyl)ethanaminehydrochloride. ESI-MS (m/z): 545/546/547 [MH]⁺.

Example 95:(S)-2-(4-((5-(((S)-1-(4-(tert-butyl)phenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-2-chlorophenoxy)propanoicAcid

The title compound was prepared following the same protocol as describedin Step 5-6, Example 73, using the (S)-1-(4-tert-butylphenyl)ethanaminehydrochloride instead of the (S)-1-(3-isopropylphenyl)ethanaminehydrochloride. ESI-MS (m/z): 561/562/563 [MH]⁺.

Example 96:(S)-2-(2-chloro-3-((5-(((S)-1-(3-cyclopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoicAcid

The title compound was prepared following the same protocol as describedin Step 5-6, Example 68, using the (S)-1-(3-cyclopropylphenyl)ethanaminehydrochloride instead of the (S)-1-(3-isopropylphenyl)ethanaminehydrochloride. ESI-MS (m/z): 545/546/547 [MH]⁺.

Example 97:(S)-2-(3-((5-(((S)-1-(4-(tert-butyl)phenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-2-chlorophenoxy)propanoicAcid

The title compound was prepared following the same protocol as describedin Step 5-6, Example 68, using the (S)-1-(4-tert-butylphenyl)ethanaminehydrochloride instead of the (S)-1-(3-isopropylphenyl)ethanaminehydrochloride. ESI-MS (m/z): 561/562/563 [MH]⁺.

Example 98:1-(3-(((S)-1-amino-1-oxopropan-2-yl)oxy)-4-chlorobenzyl)-N—((S)-1-(4-(tert-butyl)phenyl)ethyl)-2,3-dimethyl-1H-indole-5-carboxamide

A solution of(S)-2-(5-((5-(((S)-1-(4-(tert-butyl)phenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-2-chlorophenoxy)propanoicacid (20 mg, 0.036 mmol), NH₄Cl (19 mg, 0.36 mmol), HATU (14 mg, 0.036mmol) and DIEA (25 μl, 0.144 mmol) in DCM (0.5 ml) was stirred at rt for1 h. After concentration, the obtained oil was purified by reverse phaseprep-HPLC (MeOH/Acetonitrile/water) to afford a white powder (18 mg).ESI-MS (m/z): 560/561/562 [MH]⁺.

Example 99:1-(5-(((S)-1-amino-1-oxopropan-2-yl)oxy)-2-chlorobenzyl)-N—((S)-1-(4-(tert-butyl)phenyl)ethyl)-2,3-dimethyl-1H-indole-5-carboxamide

A solution of(S)-2-(3-((5-(((S)-1-(4-(tert-butyl)phenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-4-chlorophenoxy)propanoicacid (20 mg, 0.036 mmol), NH₄Cl (19 mg, 0.36 mmol), HATU (14 mg, 0.036mmol) and DIEA (25 μl, 0.144 mmol) in DCM (0.5 ml) was stirred at rt for1 h. After concentration, the obtained oil was purified by reverse phaseprep-HPLC (MeOH/Acetonitrile/water) to afford a white powder (18 mg).ESI-MS (m/z): 560/561/562 [MH]⁺.

Example 100:1-(3-(((S)-1-amino-1-oxopropan-2-yl)oxy)benzyl)-N—((S)-1-(4-(tert-butyl)phenyl)ethyl)-2,3-dimethyl-1H-indole-5-carboxamide

A solution of(S)-2-(3-((5-(((S)-1-(4-(tert-butyl)phenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoicacid (20 mg, 0.036 mmol), NH₄Cl (19 mg, 0.36 mmol), HATU (14 mg, 0.036mmol) and DIEA (25 μl, 0.144 mmol) in DCM (0.5 ml) was stirred at rt for1 h. After concentration, the obtained oil was purified by reverse phaseprep-HPLC (MeOH/Acetonitrile/water) to afford a white powder (18 mg).ESI-MS (m/z): 526 [MH]⁺.

Example 101:(S)-1-(3-(2-cyanopropan-2-yl)benzyl)-N-(1-(3-cyclopropylphenyl)ethyl)-2,3-dimethyl-1H-indole-5-carboxamide

Step 1: 2-methyl-2-(m-tolyl)propanenitrile

2-(m-tolyl)acetonitrile (3.75 g, 28.6 mmol) in dry THF (20 mL) wascooled at ice bath, and then NaH (60% in dispension, 2.9 g, 71.5 mmol)was added gradually. The mixture was stirred at room temperature for 30min, and recooled at ice bath. Mel (3.91 mL, 62.8 mmol) was then addeddropwise. The reaction mixture was stirred at room temperature for 16hr. isopropanol was carefully added to the mixture followed by ethylacetate. The organic layer was washed with water and brine, dried overanhydrous sodium sulfate. The solvent was removed and the residue waspurified by silica gel to obtain the title compound. ¹H NMR (400 MHz,CDCl₃) δ 7.28-7.24 (m, 3H), 7.11 (s, 1H), 2.36 (s, 3H), 1.70 (s, 6H).

Step 2: 2-(3-(bromomethyl)phenyl)-2-methylpropanenitrile

The title compound was prepared following the same general protocol asdescribed in Step 2, Example 35, using2-methyl-2-(m-tolyl)propanenitrile.

Step 3: Allyl1-(3-(2-cyanopropan-2-yl)benzyl)-2,3-dimethyl-1H-indole-5-carboxylate

The title compound was prepared following the same general protocol asdescribed in Step 2, Example 1, using2-(3-(bromomethyl)phenyl)-2-methylpropanenitrile and allyl2,3-dimethyl-1H-indole-5-carboxylate. ESI-MS (m/z): 387 [M+H]⁺.

Step 4:1-(3-(2-cyanopropan-2-yl)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicAcid

The mixture of allyl1-(3-(2-cyanopropan-2-yl)benzyl)-2,3-dimethyl-1H-indole-5-carboxylate(0.688 g, 1.78 mmol) and morpholine (1.6 mL, 17.8 mmol) in THF (5 mL)was degassed and then Pd(PPh₃)₄ (0.21 g, 0.18 mmol) was added. Themixture was stirred at room temperature for 1 h. The solvent was removedand the residue was dissolved in Methanol and acidified to pH4. Thesolvent was removed and the residue was purified by silica gel to obtainthe title compound. ESI-MS (m/z): 347 [M+H]⁺.

Step 5:(S)-1-(3-(2-cyanopropan-2-yl)benzyl)-N-(1-(3-cyclopropylphenyl)ethyl)-2,3-dimethyl-1H-indole-5-carboxamide

The title compound was prepared following the same general protocol asdescribed in Step 4, Example 1, using(S)-1-(3-cyclopropylphenyl)ethanamine hydrochloride and1-(3-(2-cyanopropan-2-yl)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. ESI-MS (m/z): 490 [M+H]⁺.

Example 102:(S)-1-(3-(1-amino-2-methyl-1-oxopropan-2-yl)benzyl)-N-(1-(3-cyclopropylphenyl)ethyl)-2,3-dimethyl-1H-indole-5-carboxamideand(S)-2-(3-((5-((1-(3-cyclopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenyl)-2-methylpropanoicAcid

To(S)-1-(3-(2-cyanopropan-2-yl)benzyl)-N-(1-(3-cyclopropylphenyl)ethyl)-2,3-dimethyl-1H-indole-5-carboxamide(0.1 g, 0.2 mmol) in ethanol added NaOH (5 N, 1 mL). The mixture washeated at 130° C. oil bath for 2 days. The mixture was cooled to roomtemperature and acidified to pH 4. The solvent was removed and residuewas purified by preparative-HPLC to obtain the title compounds.(S)-1-(3-(1-amino-2-methyl-1-oxopropan-2-yl)benzyl)-N-(1-(3-cyclopropylphenyl)ethyl)-2,3-dimethyl-1H-indole-5-carboxamideESI-MS (m/z): 508 [M+H]⁺:(S)-2-(3-((5-((1-(3-cyclopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenyl)-2-methylpropanoicacid. ESI-MS (m/z): 509 [M+H]⁺.

Example 103:(2S)-2-(3-(1-(5-(((S)-1-(3-cyclopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)ethyl)phenoxy)propanoicAcid

Step 1: (S)-methyl 2-(3-ethylphenoxy)propanoate

To 3-ethylphenol (3.42 g, 28 mmol) in THF (20 mL) at ice bath was addedtriphenylphosphine (9.5 g, 36.4 mmol) and then (R)-methyl2-hydroxypropanoate (2.94 mL, 31 mmol). And then DIAD (8.2 mL, 42 mmol)was added dropwise to the above cole solution. The mixture was stirredat room temperature for 16 hr. The solvent was removed and the residuewas purified by silica gel to obtain the title compound.

Step 2:(2S)-methyl 2-(3-(1-bromoethyl)phenoxy)propanoate

The title compound was prepared following the same general protocol asdescribed in Step 2, Example 35, using (S)-methyl2-(3-ethylphenoxy)propanoate.

Step 3: Allyl1-(1-(3-(((S)-1-methoxy-1-oxopropan-2-yl)oxy)phenyl)ethyl)-2,3-dimethyl-1H-indole-5-carboxylate

The title compound was prepared following the same general protocol asdescribed in Step 2, Example 1, using (2S)-methyl2-(3-(1-bromoethyl)phenoxy)propanoate and allyl2,3-dimethyl-1H-indole-5-carboxylate. ESI-MS (m/z): 436 [M+H]⁺.

Step 4:1-(1-(3-(((S)-1-methoxy-1-oxopropan-2-yl)oxy)phenyl)ethyl)-2,3-dimethyl-1H-indole-5-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 4. Example 36, using allyl1-(1-(3-(((S)-1-methoxy-1-oxopropan-2-yl)oxy)phenyl)ethyl)-2,3-dimethyl-1H-indole-5-carboxylate.ESI-MS (m/z): 396 [M+H]⁺.

Step 5: (2S)-methyl2-(3-(1-(5-(((S)-1-(3-cyclopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)ethyl)phenoxy)propanoate

The title compound was prepared following the same general protocol asdescribed in Step 4, Example 1, using(S)-1-(3-cyclopropylphenyl)ethanamine hydrochloride and1-(3-(2-cyanopropan-2-yl)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. ESI-MS (m/z): 539 [M+H]⁺.

Step 6:(2S)-2-(3-(1-(5-(((S)-1-(3-cyclopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)ethyl)phenoxy)propanoicAcid

NaOH (2 N, 0.1 mL, 0.2 mmol) was added to (2S)-methyl2-(3-(1-(5-(((S)-1-(3-cyclopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)ethyl)phenoxy)propanoate(0.03 g, 0.06 mmol) in Methanol (0.5 mL). The reaction mixture wasacidified to pH 4. The solvent was removed and the residue was purifiedby preparative-HPLC to obtain the title compound. ESI-MS (m/z): 525[M+H]⁺.

Example 104:(2S)-2-(3-(1-(5-(((S)-1-(4-(tert-butyl)phenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)ethyl)phenoxy)propanoicAcid

The title compound was prepared following the same general protocol asdescribed in Step 5-6. Example 103, using(S)-1-(4-(tert-butyl)phenyl)ethanamine hydrochloride. ESI-MS (m/z): 541[M+H]⁺.

Example 105:(S)-2-(3-((5-(((S)-1-(3-isopropoxyphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoicAcid

Step 1: (S)-methyl 2-(m-tolyloxy)propanoate

To a solution of m-cresol (5.0 g, 46 mmol, 1 equiv), methyl-D(+) lactate(4.8 g, 46 mmol, 1 equiv) and PPh₃ (14.5 g, 55.2 mmol, 1.2 equiv) inanhydrous THF (200 mL) under argon and at 0° C., was added dropwise DIAD(9.96 g, 48.2 mmol, 1.5 equiv). The reaction mixture was stirred at 0°C. until room temperature overnight. The crude mixture was dissolved inAcOEt (200 mL) and washed with a 0.5 N HCl aqueous solution (×2), asaturated NaHCO₃ solution (×2), brine and then dried over Na₂SO₄. Afterfiltration, solvent was evaporated. The crude product was purified byflash chromatography on silica gel (AcOEt/hexane 0->60%) to obtain thetitle compound.

Step 2: (S)-methyl 2-(3-(bromomethyl)phenoxy)propanoate

To a 250 mL round-bottom flask was (S)-methyl 2-(m-tolyloxy)propanoate(2.0 g, 10.3 mmol, 1 equiv), NBS (1.83 g, 10.3 mmol, 1 equiv), AIBN (169mg, 1.03 mmol, 0.1 equiv) and CCl₄ (100 mL). The reaction mixture wasrefluxed for 16 h at 80° C. The completion of the reaction was monitoredby analytical HPLC. The reaction mixture was allowed to cool to roomtemperature. The crude mixture was dissolved in AcOEt (100 mL) andwashed with a 0.5N HCl aqueous solution (×2), a saturated NaHCO₃solution (×2) and brine, dried over Na₂SO₄. The filtrate wasconcentrated to obtain the crude product which was purified by flashchromatography (AcOEt/Hexane 0->60%) to obtain the title compound.

Step 3: (S)-allyl1-(3-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylate

To a solution of allyl 2,3-dimethyl-1H-indole-5-carboxylate (1.0 g, 4.4mmol, 1 equiv) and (S)-methyl 2-(3-(bromomethyl)phenoxy)propanoate (1.30g, 4.84 mmol, 1.1 equiv) in anhydrous DMF (30 mL) under argon atmospherewas added sodium hydride (211 mg, 8.8 mmol, 2 equiv) in small portions.The mixture was stirred 2 h at room temperature. The reaction mixturewas then quenched slowly with a solution of HCl 0.5 N. The residue wasdissolved in AcOEt, washed with a saturated NaHCO₃ solution and brine,dried over MgSO₄. The crude was purified by flash chromatography(AcOEt/Hexane 0->60%) to afford the title compound.

Step 4:(S)-1-(3-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicAcid

A mixture of (S)-allyl1-(3-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylate(1.0 g, 2.37 mmol, 1 equiv), Pd(PPh₃)₄ (277 mg, 0.24 mmol, 0.1 equiv),and morpholine (2 mL, 23.7 mmol, 10 equiv) in anhydrous THF (30 mL) wasstirred at room temperature under argon atmosphere for 16 h. Thecompletion of the reaction was monitored by anal. HPLC. The crudemixture was dissolved in AcOEt (100 mL) and washed with a 0.5N HClaqueous solution (×2) and brine, then dried over Na₂SO₄. The filtratewas concentrated to obtain the crude product which was purified by flashchromatography (AcOEt/Hexane 0->60%) to obtain the title compound.

Step 5: (S)-methyl2-(3-((5-(((S)-1-(3-isopropoxyphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoate

To a solution of(S)-1-(3-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid (50 mg, 0.13 mmol, 1 equiv) in DCM (2 mL) was added(S)-1-(3-isopropoxyphenyl)ethanamine (34 mg, 0.16 mmol, 1.2 equiv), DIEA(70 μL, 0.39 mmol, 3 equiv) and HATU (50 mg, 0.13 mmol, 1 equiv). Thereaction mixture was stirred 2 h at room temperature. The solvent wasremoved in vacuo. The residue was dissolved in AcOEt and washed with a0.5N HCl aqueous solution, a saturated NaHCO₃ solution and brine, driedover MgSO₄. The filtrate was concentrated to obtain the crude productwhich was purified by flash chromatography (AcOEt/Hexane 0->50%) toobtain the title compound.

Step 6:(S)-2-(3-((5-(((S)-1-(3-isopropoxyphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoicAcid

To a solution of (S)-methyl 2-(3-((5-(((S)-1-(3-isopropoxyphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoate (70 mg,0.13 mmol, 1 equiv) in THF (2 mL) was added a 1 N LiOH aqueous solutionof (1 mL). The reaction mixture was stirred 6 h at room temperature,then acidified with a 0.5 N HCl aqueous solution. The mixture wasfiltered and the precipate was dissolved in methanol and concentrated toobtain the crude product which was purified by prep. HPLC(MeOH/Acetonitrile/water 0.1% TFA) to obtain the title compound. ESI-MS(m/z): 529 [M+H]⁺.

Example 106:(S)-2-(3-((5-(((S)-1-(3-(tert-butyl)phenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoicAcid

The title compound was prepared following the same protocol as describedin Steps 4-6, Example 105, using (S)-1-(3-(tert-butyl)phenyl)ethanamineinstead of the (S)-1-(3-isopropoxyphenyl)ethanamine. ESI-MS (m/z): 527[M+H]⁺.

Example 107:(S)-2-(3-((5-(((S)-1-(4-bromophenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoicAcid

The title compound was prepared following the same protocol as describedin Steps 4-6, Example 105, using (S)-1-(4-bromophenyl)ethanamine insteadof the (S)-1-(3-isopropoxyphenyl)ethanamine. ESI-MS (m/z): 549 [M+H]⁺.

Example 108:(S)-2-(3-((2,3-dimethyl-5-(((S)-1-(4-(trifluoromethyl)phenyl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)phenoxy)propanoic Acid

The title compound was prepared following the same protocol as describedin Steps 4-6, Example 105, using(S)-1-(3-(trifluoromethyl)phenyl)ethanamine instead of the(S)-1-(3-isopropoxyphenyl)ethanamine. ESI-MS (m/z): 539 [M+H]⁺.

Example 109:(S)-2-(3-((5-(((S)-1-(3-chlorophenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoicAcid

The title compound was prepared following the same protocol as describedin Steps 4-6, Example 105, using (S)-1-(3-chlorophenyl)ethanamineinstead of the (S)-1-(3-isopropoxyphenyl)ethanamine. ESI-MS (m/z): 505[M+H]⁺.

Example 110:(S)-2-(3-((5-(((S)-1-(4-chlorophenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoicAcid

The title compound was prepared following the same protocol as describedin Steps 4-6, Example 105, using (S)-1-(4-chlorophenyl)ethanamineinstead of the (S)-1-(3-isopropoxyphenyl)ethanamine. ESI-MS (m/z): 505[M+H]⁺.

Example 111:(S)-2-(3-((5-(((S)-1-(2-chlorophenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoicAcid

The title compound was prepared following the same protocol as describedin Steps 4-6, Example 105, using (S)-1-(2-chlorophenyl)ethanamineinstead of the (S)-1-(3-isopropoxyphenyl)ethanamine. ESI-MS (m/z): 505[M+H]⁺.

Example 112:(S)-2-(5-((5-(((S)-1-(4-(tert-butyl)phenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-2-methoxyphenoxy)propanoicAcid

The title compound was prepared following the same protocol as describedin Steps 4-6, Example 105, using (S)-1-(4-(tert-butyl)phenyl)ethanamineinstead of the (S)-1-(3-isopropoxyphenyl)ethanamine. ESI-MS (m/z): 557[M+H]⁺.

Example 113:(S)-2-(5-((5-(((S)-1-(3-cyclopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-2-methoxyphenoxy)propanoicAcid

The title compound was prepared following the same protocol as describedin Steps 4-6, Example 105, using (S)-1-(3-cyclopropylphenyl)ethanamineinstead of the (S)-1-(3-isopropoxyphenyl)ethanamine. ESI-MS (m/z): 541[M+H]⁺.

Example 114:(S)-2-(3-((5-(((S)-1-(4-(tert-butyl)phenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-4-fluorophenoxy)propanoicAcid

The title compound was prepared following the same protocol as describedin Steps 4-6, Example 105, using (S)-1-(4-(tert-butyl)phenyl)ethanamineinstead of the (S)-1-(3-isopropoxyphenyl)ethanamine. ESI-MS (m/z): 545[M+H]⁺.

Example 115:(S)-2-(5-((5-(((S)-1-(4-(tert-butyl)phenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-2-fluorophenoxy)propanoicAcid

The title compound was prepared following the same protocol as describedin Steps 4-6, Example 105, using (S)-1-(4-(tert-butyl)phenyl)ethanamineinstead of the (S)-1-(3-isopropoxyphenyl)ethanamine. ESI-MS (m/z): 545[M+H]⁺.

Example 116:(S)-2-(5-((5-(((S)-1-(3-cyclopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-2-fluorophenoxy)propanoicAcid

The title compound was prepared following the same protocol as describedin Steps 4-6, Example 105, using (S)-1-(3-cyclopropylphenyl)ethanamineinstead of the (S)-1-(3-isopropoxyphenyl)ethanamine. ESI-MS (m/z): 529[M+H]⁺.

Example 117:(S)-2-(3-((5-(((S)-1-(4-methoxyphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoicAcid

The title compound was prepared following the same protocol as describedin Steps 4-6, Example 105, using (S)-1-(4-methoxyphenyl)ethanamineinstead of the (S)-1-(3-isopropoxyphenyl)ethanamine. ESI-MS (m/z): 501[M+H]⁺.

Example 118:(2S)-2-(4-(1-(5-(((S)-1-(4-(tert-butyl)phenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)ethyl)phenoxy)propanoicAcid

Step 1: 4-Ethylphenyl Acetate

To a stirred solution of 4-ethylphenol (3.38 g, 27.67 mmol) in DCM (50mL) in an ice bath was added TEA (7.2 mL, 55.34 mmol), followed by thedropwise addition of acetyl chloride (2.2 mL, 30.44 mmol). The mixturewas stirred at room temperature for 30 min. The reaction mixture wasquenched with water (40 mL) and extracted with DCM (3×50 mL). Thecombined organic layers were washed with brine, dried over Na₂SO₄,filtered and concentrated under reduced pressure and purified by silicagel chromatography to obtain the title compound.

Step 2: 4-(1-Bromoethyl)phenyl Acetate

The title compound was prepared following the same general protocol asdescribed in Step 2, Example 35, using 4-ethylphenyl acetate.

¹H NMR (400 MHz, CDCl₃) δ 7.45 (d, J=8.8 Hz, 2H), 7.06 (d, J=8.8 Hz,2H), 5.21 (q, J=7.2 Hz, 1H), 2.99 (s, 3H), 2.04 (d, J=6.8 Hz, 3H).

Step 3: Allyl1-(1-(4-hydroxyphenyl)ethyl)-2,3-dimethyl-1H-indole-5-carboxylate

The title compound was prepared following the same general protocol asdescribed in Step 2, Example 1, using 4-(1-bromoethyl)phenyl acetate andallyl 2,3-dimethyl-1H-indole-5-carboxylate.

To the above reaction mixture was added saturated Na₂CO₃ solution (20mL) and the mixture was stirred at room temperature for 1 h. The mixturewas diluted with EtOAc, followed by the addition of a saturated NH₄Clsolution. The aqueous layer was removed and the organic layer was washedwith water and then brine and dried over Na₂SO₄. The solvent was removedunder reduced pressure and the residue was purified by silica gelchromatography to obtain the title compound. ESI-MS (m/z): 350 [M+H]⁺.

Step 4: Allyl1-(1-(4-(((S)-1-methoxy-1-oxopropan-2-yl)oxy)phenyl)ethyl)-2,3-dimethyl-1H-indole-5-carboxylate

To allyl1-(1-(4-hydroxyphenyl)ethyl)-2,3-dimethyl-1H-indole-5-carboxylate (0.286g, 0.82 mmol) in THF (0.8 mL) in an ice bath was addedtriphenylphosphine (0.28 g, 1.07 mmol) and then (R)-methyl2-hydroxypropanoate (0.093 mL, 0.98 mmol). DIAD (0.24 mL, 1.23 mmol) wasadded dropwise to the cold solution. The mixture was stirred at roomtemperature for 16 hr. The solvent was removed and the residue waspurified by silica gel chromatography to obtain the title compound.ESI-MS (m/z): 436 [M+H]⁺.

Step 5:1-(1-(4-(((S)-1-Methoxy-1-oxopropan-2-yl)oxy)phenyl)ethyl)-2,3-dimethyl-1H-indole-5-carboxylicAcid

The mixture of allyl1-(1-(4-(((S)-1-methoxy-1-oxopropan-2-yl)oxy)phenyl)ethyl)-2,3-dimethyl-1H-indole-5-carboxylate(0.55 g, 1.26 mmol) and morpholine (1.0 mL, 12.6 mmol) in THF (5 mL) wasdegassed and then Pd(PPh₃)₄ (0.15 g, 0.13 mmol) was added. The mixturewas stirred at room temperature for 1 h. The solvent was removed and theresidue was dissolved in Methanol and acidified to pH 4. The solvent wasremoved and the residue was purified by silica gel chromatography toobtain the title compound. ESI-MS (m/z): 396 [M+H]⁺.

Step 6: (25)-Methyl2-(4-(1-(5-(((S)-1-(4-(tert-butyl)phenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)ethyl)phenoxy)propanoate

The title compound was prepared following the same general protocol asdescribed in Step 5, Example 35, using(S)-1-(4-(tert-butyl)phenyl)ethanamine instead of(S)-1-(3-bromophenyl)ethylamine and1-(1-(4-(((S)-1-methoxy-1-oxopropan-2-yl)oxy)phenyl)ethyl)-2,3-dimethyl-1H-indole-5-carboxylicacid instead of1-(4-(1-(methoxycarbonyl)cyclopropyl)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid′

Step 7:(2S)-2-(4-(1-(5-(((S)-1-(4-(tert-butyl)phenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)ethyl)phenoxy)propanoicAcid

A solution of (25)-methyl2-(4-(1-(5-(((S)-1-(4-(tert-butyl)phenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)ethyl)phenoxy)propanoate(˜0.07 mmol) and NaOH (2 M, 0.2 mL) in MeOH (2 mL) and DMF (1 mL) wasstirred at rt for 5 h. It was neutralized and purified by preparativeHPLC to yield the title compound as a white solid. ESI-MS (m/z): 541[M+H]⁺.

Example 119:(2S)-2-(4-(1-(5-(((S)-1-(3-Cyclopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)ethyl)phenoxy)propanoicAcid

The title compound was prepared following the same general protocol asdescribed in the previous example. ESI-MS (m/z): 525 [M+H]⁺.

Example 120:(S)-1-(3-((5-((1-(3-Cyclopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenyl)cyclopropanecarboxylicAcid

Step 1: 1-(m-Tolyl)cyclopropanecarbonitrile

To a stirred solution of 2-(m-tolyl)acetonitrile (4.2 g, 32 mmol) intoluene (15 mL) was added sodium hydroxide (30 mL, 50% w/w in water, 375mmol), 1-bromo-2-chloroethane (9.3 mL, 112 mmol) and (n-Bu)₄Br (0.5 g,1.55 mmol). The mixture was heated at 60° C. overnight. After cooling toroom temperature, the reaction mixture was diluted with water (40 mL)and extracted with EtOAc (3×50 mL). The combined organic layers werewashed with brine, dried over Na₂SO₄, filtered and concentrated underreduced pressure and purified by silica gel chromatography to obtain thetitle compound.

¹H NMR (400 MHz, CDCl₃) δ 7.26-7.22 (m, 1H), 7.13-7.05 (m, 3H), 2.36 (s,3H), 1.72-1.68 (m, 2H), 1.41-1.38 (m, 2H).

Step 2: 1-(3-(Bromomethyl)phenyl)cyclopropanecarbonitrile

The title compound was prepared following the same general protocol asdescribed in Step 2, Example 35, using1-(m-tolyl)cyclopropanecarbonitrile.

Step 3: Allyl1-(3-(1-cyanocyclopropyl)benzyl)-2,3-dimethyl-1H-indole-5-carboxylate

The title compound was prepared following the same general protocol asdescribed in Step 2, Example 1, using1-(3-(bromomethyl)phenyl)cyclopropanecarbonitrile and allyl2,3-dimethyl-1H-indole-5-carboxylate

Step 4:1-(3-(1-Cyanocyclopropyl)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicAcid

The mixture of allyl1-(3-(1-cyanocyclopropyl)benzyl)-2,3-dimethyl-1H-indole-5-carboxylate(375 mg, 0.98 mmol) and morpholine (0.8 mL, 9.2 mmol) in THF (8 mL) wasdegassed and then Pd(PPh₃)₄ (117 mg, 0.10 mmol) was added. The mixturewas stirred at room temperature for 1 h. The solvent was removed and theresidue was dissolved in Methanol and acidified to pH 4. The precipitatewas collected and washed with water to obtain the title compound.

Step 5:(S)-1-(3-(1-Cyanocyclopropyl)benzyl)-N-(1-(3-cyclopropylphenyl)ethyl)-2,3-dimethyl-1H-indole-5-carboxamide

The title compound was prepared following the same general protocol asdescribed in Step 5, Example 35, using1-(3-(1-cyanocyclopropyl)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid and (S)-1-(3-cyclopropylphenyl)ethanamine.

Step 6:(S)-1-(3-((5-((1-(3-Cyclopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenyl)cyclopropanecarboxylicAcid

To a solution of(S)-1-(3-(1-Cyanocyclopropyl)benzyl)-N-(1-(3-cyclopropylphenyl)ethyl)-2,3-dimethyl-1H-indole-5-carboxamide(˜0.2 mmol) in Ethanol was added NaOH (5 N, 1 mL). The mixture washeated at 130° C. in an oil bath for 14 days. The mixture was cooled toroom temperature and acidified to pH 4. The solvent was removed and theresidue was purified by preparative-HPLC to obtain the title compound.ESI-MS (m/z): 507 [M+H]⁺.

Example 121:((S)-3-((5-((1-(3-Cyclopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)benzoicAcid

Step 1: Allyl1-(3-(methoxycarbonyl)benzyl)-2,3-dimethyl-1H-indole-5-carboxylate

The title compound was prepared following the same general protocol asdescribed in Step 2, Example 1, using methyl 3-(bromomethyl)benzoate andallyl 2,3-dimethyl-1H-indole-5-carboxylate.

Step 4:1-(3-(Methoxycarbonyl)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic Acid

The mixture of allyl1-(3-(methoxycarbonyl)benzyl)-2,3-dimethyl-1H-indole-5-carboxylate (133mg, 0.35 mmol) and morpholine (0.3 mL, 3.4 mmol) in THF (4 mL) wasdegassed and then Pd(PPh₃)₄ (41 mg, 0.035 mmol) was added. The mixturewas stirred at room temperature for 1 h. The solvent was removed and theresidue was dissolved in Methanol and acidified to pH 4. The precipitatewas collected and washed with water to obtain the title compound.

Step 5: (S)-Methyl3-((5-((1-(3-cyclopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)benzoate

The title compound was prepared following the same general protocol asdescribed in Step 5, Example 35, using1-(3-(methoxycarbonyl)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acidand (S)-1-(3-cyclopropylphenyl)ethanamine.

Step 6:((S)-3-((5-((1-(3-Cyclopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)benzoicAcid

A solution of (S)-Methyl3-((5-((1-(3-cyclopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)benzoate(˜0.07 mmol) and NaOH (2 M, 0.5 mL) in MeOH (2 mL) and DMSO (1 mL) wasstirred at rt for 15 h. It was neutralized and purified by preparativeHPLC to yield the title compound as a white solid. ESI-MS (m/z): 467[M+H]⁺.

Example 122:(S)-1-(3-Carbamoylbenzyl)-N-(1-(3-cyclopropylphenyl)ethyl)-2,3-dimethyl-1H-indole-5-carboxamide

The title compound was prepared following the same general protocol asdescribed in Step 5, Example 35. ESI-MS (m/z): 466 [M+H]⁺.

Example 123:(S)-2-(5-((5-(((S)-1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-2-methoxyphenoxy)propanoicAcid

The title compound was prepared following the same protocol as describedin Step 5, Example 36, using the (S)-1-(3-isopropylphenyl)ethanaminehydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanaminehydrochloride, followed by an ester hydrolysis step as outlined in Step6, example 36.

Example 124:(S)-2-(2-fluoro-5-((5-(((S)-1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoicAcid

The title compound was prepared following the same protocol as describedin Step 5, Example 36, using the (S)-1-(3-isopropylphenyl)ethanaminehydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanaminehydrochloride and(S)-1-(4-fluoro-3-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid instead of the1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylicacid, followed by an ester hydrolysis step as outlined in Step 6,example 36.

SYNTHETIC EXAMPLES Compounds of Formula (IB) Example 1:(S)-4′-((5-(1-(4-Bromophenyl)ethylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

Step 1: tert-Butyl 2-bromobenzoate

To a solution of 2-bromobenzoic acid (8.08 g, 40.2 mmol), DMAP (0.492 g,8.0 mmol) and t-BuOH (9.3 mL, 80.4 mmol) in dry DCM (300 mL) underargon, was added DCC (9.96 g, 48.2 mmol). The reaction mixture wasstirred at room temperature for 20 h. The resulting mixture was filteredand the filtrate was evaporated in vacuo. The crude mixture wasdissolved in AcOEt (300 mL) and washed with saturated aqueous NaHCO₃(261), brine and then dried over Na₂SO₄. After filtration, solvent wasevaporated. The crude product was purified by flash chromatography onsilica gel (AcOEt/hexane 0->30%) to obtain the title compound.

Step 2: tert-Butyl 4′-methylbiphenyl-2-carboxylate

To a 350 mL high-pressure vial was added tert-butyl 2-bromobenzoate(5.142 g, 20.0 mmol), p-tolylboronic acid (4.08 g, 30.0 mmol), Pd(PPh₃)₄(3.47 g, 3.0 mmol), potassium carbonate (8.29 g, 60.0 mmol) and dioxanewith water (4:1, 200 mL). The mixture was degassed for 5 min and sealed.The mixture was heated at 100° C. for 40 min wherein analytical HPLCanalysis indicated the completion of the reaction. The mixture wasfiltered through Celite and MeOH was used to wash the Celite pad. Thesolvent was removed and the crude was purified by flash chromatography(AcOEt/Hexane 0->30%) to obtain the title compound.

Step 3: tert-butyl 4′-(bromomethyl)biphenyl-2-carboxylate

To a 500 mL round-bottom flask was added tert-butyl4′-methylbiphenyl-2-carboxylate (7.04 g, 26.23 mmol), NBS (5.14 g, 28.85mmol), AIBN (0.43 g, 2.62 mmol) and CCl₄ (200 mL). The reaction mixturewas refluxed for 2 h at 100° C. The completion of the reaction wasmonitored by analytical HPLC. The reaction mixture was allowed to coolto room temperature and filtered. The filtrate was concentrated toobtain the crude product which was purified by flash chromatography(AcOEt/Hexane 0->30%) to obtain the title compound.

Step 4: tert-Butyl 1-(4-(ethoxycarbonyl)phenyl)hydrazinecarboxylate

To a 350 mL high-pressure vial was added ethyl 4-bromobenzoate (12.92 g,56.4 mmol), t-butyl carbazate (14.91 g, 112.8 mmol), Pd₂(dba)₃ (0.516 g,0.56 mmol), dppf (0.938 g, 1.69 mmol), Cs₂CO₃ (18.4 g, 56.4 mmol), anddry toluene (113 mL). The reaction mixture was degassed for 5 min,sealed and heated to 100° C. for 16 h. The completion of the reactionwas monitored by analytical HPLC. The reaction mixture was allowed tocool to room temperature, diluted with DCM, filtered and the filtratewas concentrated. The crude was then purified by flash chromatography(AcOEt/Hexane (0->30%) to afford the desired product. ESI-MS (m/z): 265[M+H—NH₃]⁺, 225 [M+H-tBu]⁺, 181 [M+H-Boc]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ(ppm) 1.31 (t, J=7.1 Hz, 3H, CH₃ ethyl), 1.50 (s, 9H, CH₃ Boc), 4.28 (q,J=7.1 Hz, 2H, CH₂ ethyl), 5.14 (s, 2H, NH₂), 7.70 (dt, J=8.8, 2.2 Hz,2H, H₂ and H₆ phenyl), 7.87 (dt, J=8.8, 2.2 Hz, 2H, H₃ and H₅ phenyl).

Step 5: Ethyl 2,3-dimethyl-1H-indole-5-carboxylate

A mixture of tert-butyl 1-(4-(ethoxycarbonyl)phenyl)hydrazinecarboxylate(5.27 g, 18.8 mmol), butan-2-one (2.53 mL, 28.2 mmol), and TsOHmonohydrate (21.5 g, 112.8 mmol) in toluene (300 mL) was heated at 80°C. for 2 h. The reaction mixture was allowed to cool to room temperatureand filtered. The filtrate was concentrated and then purified by flashchromatography (AcOEt/Hexane 5%) to obtain the title compound. ESI-MS(m/z): 218 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) 1.33 (t, J=7.2 Hz,3H, CH₃ ethyl), 2.18 (s, 3H, CH₃), 2.32 (s, 3H, CH₃), 4.29 (q, J=7.2 Hz,2H, CH₂ ethyl), 7.28 (dd, J=8.4, 0.4 Hz, 1H, H₇ indole), 7.64 (dd,J=8.4, 1.6 Hz, 1H, H₆ indole), 8.05 (m, 1H, H₄ indole).

Step 6: Ethyl1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylate

To a mixture of ethyl 2,3-dimethyl-1H-indole-5-carboxylate (1.493 g,6.87 mmol) in dry DMF (10 mL) at 0° C. under argon was added NaH (0.3 g,60% dispersion in mineral oil, 7.56 mmol) in portions. The reactionmixture was stirred at rt for 30 min and then re-cooled to 0° C.Tert-butyl 4′-(bromomethyl)biphenyl-2-carboxylate (2.62 g, 7.56 mmol) inDMF (2 mL) was slowly added. The reaction mixture was stirred at rt foranother 1 h. The completion of the reaction was monitored by anal. HPLC.The reaction was quenched with MeOH, and then the solvent was removed invacuo. The crude was dissolved in AcOEt, washed with saturated aqueousNaHCO₃, brine and dried over Na₂SO₄ and filtered. The filtrate wasevaporated in vacuo to obtain the crude which was purified by flashchromatography (AcOEt/Hex 10->100%) to obtain the title compound. ESI-MS(m/z): 484 [M+H]⁺.

Step 7:1-((2′-(tert-Butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicAcid

A mixture of ethyl1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylate(3.72 g, 7.69 mmol) and NaOH (7.7 mL, 2 N, 15.4 mmol) in EtOH (30 mL)was refluxed at 100° C. for 2 h. The completion of the reaction wasmonitored by anal. HPLC. The reaction mixture was cooled to rt, thenacidified to pH-4 with 2 N HCl solution. The mixture was evaporated invacuo to obtain the crude, which was precipitated from water andfiltered to obtain the title compound. ESI-MS (m/z): 456 [M+H]⁺. ¹H NMR(400 MHz, DMSO-d₆): δ (ppm) 1.13 (s, 9H, CH₃ tBu), 2.26 (s, 3H, CH₃indole), 2.33 (s, 3H, CH₃ indole), 5.49 (s, 2H, CH₂-biphenyl), 7.01 (d,J=8 Hz, 2H, H₇ and H₉ biphenyl), 7.19 (d, J=8 Hz, 2H, H₆ and H₁₀biphenyl), 7.30 (d, J=7.6 Hz, 1H, H₇ indole), 7.40-7.47 (m, 2H, H₂ andH₄ biphenyl), 7.53 (dt, J=1.2, 7.6 Hz, 1H, H₃ biphenyl), 7.63-7.69 (m,2H H₆ indole and H₅ biphenyl), 8.13 (d, J=1.2 Hz, 1H, H₄ indole).

Step 8: (S)-tert-Butyl4′-((5-(1-(4-bromophenyl)ethylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylate

To a mixture of1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid (46 mg, 0.1 mmol) in DMF (1 mL) was added DIEA (26 mg, 0.2 mmol)and HATU (46 mg, 0.12 mmol). The mixture was stirred for 5 min, and then(S)-1-(4-bromophenyl)ethanamine (20 mg, 0.13 mmol) was added. Thereaction mixture was stirred at rt for 30 min. The completion of thereaction was monitored by anal. HPLC. The solvent was removed in vacuoto obtain the crude which was purified by flash chromatography(AcOEt/Hex 10->100%) to obtain the title compound. ESI-MS (m/z): 637/639[M+H]⁺.

Step 9:(S)-4′-((5-(1-(4-Bromophenyl)ethylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

A mixture of (S)-tert-butyl4′-((5-(1-(4-bromophenyl)ethylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylate(20 mg, 0.03 mmol) in TFA/DCM (1 mL, 30%) was stirred at rt for 2 h. Thecompletion of the reaction was monitored by anal. HPLC. The solvent wasremoved to obtain the crude which was purified by reverse phaseprep-HPLC (MeOH/Acetonitrile/water) to obtain the title compound. ESI-MS(m/z): 581/583 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) 1.48 (d, J=6.8Hz, 3H, CH₃ (4-bromophenyl)ethylcarbamoyl), 2.28 (s, 3H, CH₃ indole),2.32 (s, 3H, CH₃ indole), 5.17 (quintuplet, J=7.6 Hz, 1H, CH(4-bromophenyl)ethylcarbamoyl), 5.47 (s, 2H, CH₂-biphenyl), 6.99 (d, J=8Hz, 2H, H₇ and H₉ biphenyl), 7.24 (d, J=8 Hz, 2H, H₆ and H₁₀ biphenyl),7.31 (d, J=7.6 Hz, 1H, H₇ indole), 7.36-7.55 (m, 7H, Hz, H₃ and H₄biphenyl, H₆ indole and H 4-bromophenyl), 8.10 (d, J=1.6 Hz, 1H, H₄indole), 8.65 (d, J=8 Hz, 1H, NH amide).

Example 2:(S)-4′-((5-((1-(4-(tert-butyl)phenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

Step 1:(R)—N—((S)-1-(4-(tert-butyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide

To a solution of 4-t-butylbenzaldehyde (753 μL) in THF (8 mL) was added(R)-2-methylpropane-2-sulfinamide (500 mg) followed by Ti(OiPr)₄ (2.5mL). The resulting solution was allowed to stir at room temperature for18 h, and then quenched with saturated aqueous NH₄Cl and diluted withEtOAc. The mixture was filtered through a pad of celite, and washed withEtOAc. The layers were separated, and the organic phase was washed withbrine (2×), dried (MgSO₄) and concentrated to give the imine as a lightyellow oil (1.20 g) which was used without further purification.

To a solution of the crude imine in CH₂Cl₂ (10 mL) at −50° C. was addedMeMgBr (2.7 mL, 3.0 M in Et₂O). The reaction was maintained at −50° C.for 6 h, and then allowed to warm to room temperature overnight. After16 h, the reaction was quenched with brine and diluted with EtOAc andthe layers were separated. The organic layer was washed with brine (2×),dried (MgSO₄) and concentrated. The crude residue was purified bychromatography on silica gel (EtOAc/hex) to afford the title compound asa colorless solid (1.01 g). ESI-MS (m/z): 282 [MH]⁺

Step 2: (S)-1-(4-(tert-butyl)phenyl)ethanaminium Chloride

To a solution of(R)—N—((S)-1-(4-(tert-butyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide(977 mg) in MeOH (1.75 mL) was added conc. HCl (1.75 mL). The reactionwas aged at room temperature monitoring disappearance of startingmaterial by analytical reverse-phase HPLC. When the starting materialwas consumed, the reaction was concentrated in vacuo. The crude residuewas resuspended in MeOH (1 mL) and crashed out of solution by theaddition of Et₂O. Filtration afforded the title compound as a colorlesssolid (559 mg). ESI-MS (m/z): 161 [M+H—NH₃]⁺, 338 [2M+H—NH₃]⁺.

Step 3: (S)-tert-butyl4′-((5-((1-(4-(tert-butyl)phenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylate

To a mixture of1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid (100 mg) in DMF (2 mL) was added DIEA (116 μL) and HATU (88 mg).The mixture was stirred for 5 min, and then(S)-1-(4-(tert-butyl)phenyl)ethanaminium chloride (49 mg) was added. Thereaction mixture was stirred at rt for 30 min. The completion of thereaction was monitored by anal. HPLC. The solvent was removed in vacuoto obtain the crude which was purified by flash chromatography(AcOEt/Hex 10->100%) to obtain the title compound (120 mg). ESI-MS(m/z): 559 [M+H-tBu]⁺, 615 [M+H]⁺, 637 [M+Na]⁺.

Step 4:(S)-4′-((5-(1-(4-Bromophenyl)ethylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

A mixture of (S)-tert-butyl4′-((5-((1-(4-(tert-butyl)phenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylate(120 mg) in TFA/DCM (1 mL, 30%) was stirred at rt for 2 h. Thecompletion of the reaction was monitored by anal. HPLC. The solvent wasremoved to obtain the crude which was purified by reverse phaseprep-HPLC (MeOH/Acetonitrile/water) to obtain the title compound (70mg). ESI-MS (m/z): 559 [M+H]⁺ ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) 1.26(s, 9H), 1.49 (d, J=7.2 Hz, 3H), 2.28 (s, 3H), 2.32 (s, 3H), 5.19(quintuplet, 1H), 5.47 (s, 2H), 6.99 (d, J=8.0 Hz, 2H), 7.24 (d, J=8.0Hz, 2H), 7.29-7.39 (m, 5H), 7.39-7.49 (m, 2H), 7.53 (t, J=7.2 Hz, 1H),7.65 (d, J=8.4 Hz, 1H), 7.69 (d, J=7.6 Hz, 1H), 8.1 (s, 1H,), 8.58 (d,J=8.0 Hz, 1H).

Example 3:4′-((5-(Benzyl(methyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

Step 1: tert-Butyl4′-((5-(benzyl(methyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylate

The title compound was prepared following the same general protocol asdescribed in Step 8, Example 1, using N-methyl-1-phenylmethanamineinstead of (S)-1-(4-bromophenyl)ethanamine. ESI-MS (m/z): 559 [M+H]⁺.

Step 2:4′-((5-(Benzyl(methyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 9, Example 1. ESI-MS (m/z): 503 [M+H]⁺.

Example 4:4′-((2,3-Dimethyl-5-(3-(methylsulfonyl)benzylcarbamoyl)-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

Step 1: tert-Butyl4′-((2,3-dimethyl-5-(3-(methylsulfonyl)benzylcarbamoyl)-1H-indol-1-yl)methyl)biphenyl-2-carboxylate

The title compound was prepared following the same general protocol asdescribed in Step 8, Example 1, using(3-(methylsulfonyl)phenyl)methanamine instead of(S)-1-(4-bromophenyl)ethanamine. ESI-MS (m/z): 567 [M+H]⁺-tert-butyl.

Step 2:4′-((2,3-Dimethyl-5-(3-(methylsulfonyl)benzylcarbamoyl)-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 9, Example 1. ESI-MS (m/z): 567 [M+H]⁺.

Example 5:4′-((2,3-Dimethyl-5-(3-(trifluoromethoxy)benzylcarbamoyl)-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

Step 1: tert-Butyl4′-((2,3-dimethyl-5-(3-(trifluoromethoxy)benzylcarbamoyl)-1H-indol-1-yl)methyl)biphenyl-2-carboxylate

The title compound was prepared following the same general protocol asdescribed in Step 8, Example 1, using(3-(trifluoromethoxy)phenyl)methanamine instead of(S)-1-(4-bromophenyl)ethanamine. ESI-MS (m/z): 629 [M+H]⁺.

Step 2:4′-((2,3-Dimethyl-5-(3-(trifluoromethoxy)benzylcarbamoyl)-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 9, Example 1. ESI-MS (m/z): 573 [M+H]⁺.

Example 6:(R)-4′-((5-(1-(4-Bromophenyl)ethylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

Step 1: (R)-tert-Butyl4′-((5-(1-(4-bromophenyl)ethylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylate

The title compound was prepared following the same general protocol asdescribed in Step 8, Example 1, using (R)-1-(4-bromophenyl)ethanamineinstead of (S)-1-(4-bromophenyl)ethanamine. ESI-MS (m/z): 637/639[M+H]⁺.

Step 2:(R)-4′-((5-(1-(4-Bromophenyl)ethylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 9, Example 1. ESI-MS (m/z): 581/583 [M+H]⁺.

Example 7:4′-((5-(4-Iodobenzylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

Step 1: tert-Butyl4′-((5-(4-iodobenzylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylate

The title compound was prepared following the same general protocol asdescribed in Step 8, Example 1, using (4-iodophenyl)methanamine insteadof (S)-1-(4-bromophenyl)ethanamine. ESI-MS (m/z): 671 [M+H]⁺.

Step 2:4′-((5-(4-Iodobenzylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 9, Example 1. ESI-MS (m/z): 615 [M+H]⁺.

Example 8:4′-((5-(4-Cyanobenzylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

Step 1: tert-Butyl4′-((5-(4-cyanobenzylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylate

The title compound was prepared following the same general protocol asdescribed in Step 8, Example 1, using 4-(aminomethyl)benzonitrileinstead of (S)-1-(4-bromophenyl)ethanamine. ESI-MS (m/z): 514[M+H]⁺-tert-butyl.

Step 2:4′-((5-(4-Cyanobenzylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 9, Example 1. ESI-MS (m/z): 514 [M+H]⁺.

Example 9:4′-((5-(4-Isopropylbenzylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

Step 1: tert-Butyl4′-((5-(4-isopropylbenzylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylate

The title compound was prepared following the same general protocol asdescribed in Step 8, Example 1, using (4-isopropylphenyl)methanamineinstead of (S)-1-(4-bromophenyl)ethanamine. ESI-MS (m/z): 587 [M+H]⁺.

Step 2:4′-((5-(4-Isopropylbenzylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 9, Example 1. ESI-MS (m/z): 531 [M+H]⁺.

Example 10:4′-((2,3-Dimethyl-5-(4-(methylsulfonyl)benzylcarbamoyl)-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

Step 1: tert-Butyl4′-((2,3-dimethyl-5-(4-(methylsulfonyl)benzylcarbamoyl)-1H-indol-1-yl)methyl)biphenyl-2-carboxylate

The title compound was prepared following the same general protocol asdescribed in Step 8, Example 1, using(4-(methylsulfonyl)phenyl)methanamine instead of(S)-1-(4-bromophenyl)ethanamine. ESI-MS (m/z): 567 [M+H]⁺-tert-butyl.

Step 2:4′-((2,3-Dimethyl-5-(4-(methylsulfonyl)benzylcarbamoyl)-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 9, Example 1. ESI-MS (m/z): 567 [M+H]⁺.

Example 11:4′-((5-(4-(Dimethylamino)benzylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

Step 1: tert-Butyl4′-((5-(4-(dimethylamino)benzylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylate

The title compound was prepared following the same general protocol asdescribed in Step 8, Example 1, using4-(aminomethyl)-N,N-dimethylaniline instead of(S)-1-(4-bromophenyl)ethanamine. ESI-MS (m/z): 588 [M+H]⁺.

Step 2:4′-((5-(4-(Dimethylamino)benzylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 9, Example 1. ESI-MS (m/z): 532 [M+H]⁺.

Example 12:4′-((5-(4-Bromobenzylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

Step 1: tert-Butyl4′-((5-(4-bromobenzylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylate

The title compound was prepared following the same general protocol asdescribed in Step 8, Example 1, using (4-bromophenyl)methanamine insteadof (S)-1-(4-bromophenyl)ethanamine.

ESI-MS (m/z): 567/569, [M+H]⁺-tert-butyl.

Step 2:4′-((5-(4-Bromobenzylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 9, Example 1. ESI-MS (m/z): 567/569 [M+H]⁺.

Example 13:4′-((5-(4-tert-Butylbenzylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

Step 1: tert-Butyl4′-((5-(4-tert-butylbenzylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylate

The title compound was prepared following the same general protocol asdescribed in Step 8, Example 1, using (4-tert-butylphenyl)methanamineinstead of (S)-1-(4-bromophenyl)ethanamine. ESI-MS (m/z): 601 [M+H]⁺.

Step 2:4′-((5-(4-tert-Butylbenzylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 9, Example 1. ESI-MS (m/z): 545 [M+H]⁺.

Example 14:4′-((5-(4-Chlorobenzylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

Step 1: tert-Butyl4′-((5-(4-chlorobenzylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylate

The title compound was prepared following the same general protocol asdescribed in Step 8, Example 1, using (4-chlorophenyl)methanamineinstead of (S)-1-(4-bromophenyl)ethanamine. ESI-MS (m/z): 523[M+H]⁺-tert-butyl.

Step 2:4′-((5-(4-Chlorobenzylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 9, Example 1. ESI-MS (m/z): 523 [M+H]⁺.

Example 15:4′-((2,3-Dimethyl-5-(4-(trifluoromethoxy)benzylcarbamoyl)-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

Step 1: tert-Butyl4′-((2,3-dimethyl-5-(4-(trifluoromethoxy)benzylcarbamoyl)-1H-indol-1-yl)methyl)biphenyl-2-carboxylate

The title compound was prepared following the same general protocol asdescribed in Step 8, Example 1, using(4-(trifluoromethoxy)phenyl)methanamine instead of(S)-1-(4-bromophenyl)ethanamine. ESI-MS (m/z): 573 [M+H]⁺-tert-butyl.

Step 2:4′-((2,3-Dimethyl-5-(4-(trifluoromethoxy)benzylcarbamoyl)-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 9, Example 1. ESI-MS (m/z): 573 [M+H]⁺.

Example 16:4′-((5-(4-(Methoxycarbonyl)benzylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

Step 1: tert-Butyl4′-((5-(4-(methoxycarbonyl)benzylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylate

The title compound was prepared following the same general protocol asdescribed in Step 8, Example 1, using methyl 4-(aminomethyl)benzoateinstead of (S)-1-(4-bromophenyl)ethanamine. ESI-MS (m/z): 547[M+H]⁺-tert-butyl.

Step 2:4′-((5-(4-(Methoxycarbonyl)benzylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 9, Example 1. ESI-MS (m/z): 547 [M+H]⁺.

Example 17:4′-((2,3-Dimethyl-5-(4-sulfamoylbenzylcarbamoyl)-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

Step 1: tert-Butyl4′-((2,3-dimethyl-5-(4-sulfamoylbenzylcarbamoyl)-1H-indol-1-yl)methyl)biphenyl-2-carboxylate

The title compound was prepared following the same general protocol asdescribed in Step 8, Example 1, using 4-(aminomethyl)benzenesulfonamideinstead of (S)-1-(4-bromophenyl)ethanamine. ESI-MS (m/z): 568[M+1-1]⁺-tert-butyl.

Step 2:4′-((2,3-Dimethyl-5-(4-sulfamoylbenzylcarbamoyl)-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 9, Example 1. ESI-MS (m/z): 568 [M+H]⁺.

Example 18:4′-((2,3-Dimethyl-5-(4-(methylthio)benzylcarbamoyl)-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

Step 1: tert-Butyl4′-((2,3-dimethyl-5-(4-(methylthio)benzylcarbamoyl)-1H-indol-1-yl)methyl)biphenyl-2-carboxylate

The title compound was prepared following the same general protocol asdescribed in Step 8, Example 1, using (4-(methylthio)phenyl)methanamineinstead of (S)-1-(4-bromophenyl)ethanamine. ESI-MS (m/z): 591 [M+H]⁺.

Step 2:4′-((2,3-Dimethyl-5-(4-(methylthio)benzylcarbamoyl)-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 9, Example 1. ESI-MS (m/z): 535 [M+H]⁺.

Example 19:(S)-4′-((5-(1-(4-Methoxyphenyl)ethylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

Step 1: (S)-tert-Butyl4′-((5-(1-(4-methoxyphenyl)ethylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylate

The title compound was prepared following the same general protocol asdescribed in Step 8, Example 1, using (S)-1-(4-methoxyphenyl)ethanamineinstead of (S)-1-(4-bromophenyl)ethanamine. ESI-MS (m/z): 589 [M+H]⁺.

Step 2:(S)-4′-((5-(1-(4-Methoxyphenyl)ethylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

To a mixture of (S)-tert-butyl4′-((5-(1-(4-methoxyphenyl)ethylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylate(58.9 mg, 0.1 mmol) and 2,6-lutidine (0.13 mL, 1.15 mmol) in DCM (1 mL)at 0° C. was added TESOTf (0.17 mL, 0.75 mmol). The reaction mixture wasstirred at rt for 2 h. The completion of the reaction was monitored byanal. HPLC. The mixture was evaporated in vacuo to obtain the crudewhich was purified by prep. HPLC (MeOH/Acetonitrile/water) to obtain thetitle compound. ESI-MS (m/z): 533 [M+H]⁺.

Example 20:4′-((5-(2,4-Dimethoxybenzylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

Step 1: tert-Butyl4′-((5-(2,4-dimethoxybenzylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylate

The title compound was prepared following the same general protocol asdescribed in Step 8, Example 1, using (2,4-dimethoxyphenyl)methanamineinstead of (S)-1-(4-bromophenyl)ethanamine. ESI-MS (m/z): 605 [M+H]⁺.

Step 2:4′-((5-(2,4-Dimethoxybenzylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 2, Example 19. ESI-MS (m/z): 549 [M+H]⁺.

Example 21:(S)-4′-((5-(1-(3-Methoxyphenyl)ethylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

Step 1: (S)-tert-Butyl4′-((5-(1-(3-methoxyphenyl)ethylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylate

The title compound was prepared following the same general protocol asdescribed in Step 8, Example 1, using (S)-1-(3-methoxyphenyl)ethanamineinstead of (S)-1-(4-bromophenyl)ethanamine. ESI-MS (m/z): 589 [M+H]⁺.

Step 2:(S)-4′-((5-(1-(3-Methoxyphenyl)ethylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 2, Example 19. ESI-MS (m/z): 533 [M+H]⁺.

Example 22:4′-((5-(3,5-Dimethoxybenzylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

Step 1: tert-Butyl4′-((5-(3,5-dimethoxybenzylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylate

The title compound was prepared following the same general protocol asdescribed in Step 8, Example 1, using (3,5-dimethoxyphenyl)methanamineinstead of (S)-1-(4-bromophenyl)ethanamine. ESI-MS (m/z): 605 [M+H]⁺.

Step 2:4′-((5-(3,5-Dimethoxybenzylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 2, Example 19. ESI-MS (m/z): 549 [M+H]⁺.

Example 23:(R)-4′-((5-(1-(4-Methoxyphenyl)ethylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

Step 1: (R)-tert-Butyl4′-((5-(1-(4-methoxyphenyl)ethylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylate

The title compound was prepared following the same general protocol asdescribed in Step 8, Example 1, using (R)-1-(4-methoxyphenyl)ethanamineinstead of (S)-1-(4-bromophenyl)ethanamine. ESI-MS (m/z): 589 [M+H]⁺.

Step 2:(R)-4′-((5-(1-(4-Methoxyphenyl)ethylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 2, Example 19. ESI-MS (m/z): 533 [M+H]⁺.

Example 24:4′-((5-(3,4-Dimethoxybenzylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

Step 1: tert-Butyl4′-((5-(3,4-dimethoxybenzylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylate

The title compound was prepared following the same general protocol asdescribed in Step 8, Example 1, using (3,4-dimethoxyphenyl)methanamineinstead of (S)-1-(4-bromophenyl)ethanamine. ESI-MS (m/z): 605 [M+H]⁺.

Step 2:4′-((5-(3,4-Dimethoxybenzylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 2, Example 19. ESI-MS (m/z): 549 [M+H]⁺.

Example 25:4′-((2,3-Dimethyl-5-((2-phenylpropan-2-yl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

Step 1: tert-Butyl4′-((2,3-dimethyl-5-((2-phenylpropan-2-yl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylate

The title compound was prepared following the same general protocol asdescribed in Step 8, Example 1, using 2-phenylpropan-2-amine instead of(S)-1-(4-bromophenyl)ethanamine. ESI-MS (m/z): 573 [M+H]⁺.

Step 2:4′-((2,3-Dimethyl-5-((2-phenylpropan-2-yl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 2, Example 19. ESI-MS (m/z): 517 [M+H]⁺.

Example 26:(S)-4′-((2,3-Dimethyl-5-((1-(naphthalen-2-yl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

Step 1: (S)-tert-Butyl4′-((2,3-dimethyl-5-((1-(naphthalen-2-yl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylate

The title compound was prepared following the same general protocol asdescribed in Step 8, Example 1, using (S)-1-(naphthalen-2-yl)ethanamineinstead of (S)-1-(4-bromophenyl)ethanamine. ESI-MS (m/z): 609 [M+H]⁺.

Step 2:(S)-4′-((2,3-Dimethyl-5-((1-(naphthalen-2-yl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 9, Example 1. ESI-MS (m/z): 553 [M+H]⁺.

Example 27:(S)-4′-((5-((1-(4-Chlorophenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

Step 1: (S)-tert-Butyl4′-((5-((1-(4-chlorophenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylate

The title compound was prepared following the same general protocol asdescribed in Step 8, Example 1, using (S)-1-(4-chlorophenyl)ethanamineinstead of (S)-1-(4-bromophenyl)ethanamine. ESI-MS (m/z): 537[M+H]⁺-tert-butyl.

Step 2:(S)-4′-((5-((1-(4-Chlorophenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 9, Example 1. ESI-MS (m/z): 537 [M+H]⁺.

Example 30:(S)-4′-((5-((1-(3-Bromophenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

Step 1: (S)-tert-Butyl4′-((5-((1-(3-bromophenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylate

The title compound was prepared following the same general protocol asdescribed in Step 8, Example 1, using (S)-1-(3-bromophenyl)ethanaminewas used instead of (S)-1-(4-bromophenyl)ethanamine. ESI-MS (m/z):659/661 [M+H]⁺.

Step 2:(S)-4′-((5-((1-(3-Bromophenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 9, Example 1. ESI-MS (m/z): 581/583 [M+H]⁺.

Example 31:4′-((2,3-Dimethyl-5-((2-oxo-2-phenylethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

Step 1: tert-Butyl4′-((2,3-dimethyl-5-(2-oxo-2-phenylethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylate

The title compound was prepared following the same general protocol asdescribed in Step 8, Example 1, using 2-amino-1-phenylethanone insteadof (S)-1-(4-bromophenyl)ethanamine. ESI-MS (m/z): 573 [M+H]⁺.

Step 2:4′-((2,3-Dimethyl-5-((2-oxo-2-phenylethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 9, Example 1. ESI-MS (m/z): 517 [M+H]⁺.

Example 34:1-((2′-Cyano-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-N-(1-phenylpropyl)-1H-indole-5-carboxamide

Step 1: 4′-Methyl-[1,1′-biphenyl]-2-carbonitrile

The title compound was prepared following the same protocol as describedin Step 2, Example 1, using 2-bromobenzonitrile instead of thetert-butyl 2-bromobenzoate. ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) 2.38 (s,3H, CH₃), 7.34 (d, J=8 Hz, 2H, H₇ and H₈ biphenyl), 7.47 (d, J=8 Hz, 2H,H₅ and H₆ biphenyl), 7.55 (dt, J=1.2, 7.6 Hz, 1H, H₄ biphenyl), 7.59 (m,1H, H₂ biphenyl), 7.77 (dt, J=1.2, 7.6 Hz, 1H, H₃ biphenyl), 7.93 (m,1H, H₅ biphenyl).

Step 2: 4′-(Bromomethyl)-[1,1′-biphenyl]-2-carbonitrile

The title compound was prepared following the same protocol as describedin Step 3, Example 1, using 4′-methyl-[1,1′-biphenyl]-2-carbonitrileinstead of the tert-butyl 4′-methylbiphenyl-2-carboxylate and benzoylperoxide instead of AIBN. ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) 4.79 (s,2H, CH₂), 7.55-7.68 (m, 6H, Hz, H₄, H₅, H₆, H₇ and H₈ biphenyl), 7.77(t, J=7.2 Hz, 1H, H₃ biphenyl), 7.93 (d, J=7.2 Hz, 1H, H₅ biphenyl).

Step 3: Ethyl1-((2′-cyano-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylate

The title compound was prepared following the same protocol as describedin Step 6, Example 1, using4′-(Bromomethyl)-[1,1′-biphenyl]-2-carbonitrile instead of thetert-butyl 4′-(bromomethyl)biphenyl-2-carboxylate. ESI-MS (m/z): 409[M+H]⁺.

Step 4:1-((2′-Cyano-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicAcid

The title compound was prepared following the same protocol as describedin Step 7, Example 1, using ethyl1-((2′-cyano-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylateinstead of the ethyl1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylate.ESI-MS (m/z): 381 [M+H]⁺.

Step 5:1-((2′-Cyano-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-N-(1-phenylpropyl)-1H-indole-5-carboxamide

The title compound was prepared following the same protocol as describedin Step 8, Example 1, using1-((2′-cyano-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid instead of the1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid, and 1-phenylpropan-1-amine instead of the(S)-1-(4-bromophenyl)ethanamine. ESI-MS (m/z): 498 [M+H]⁺.

Example 35:(S)—N-(1-(4-Bromophenyl)ethyl)-1-((2′-cyano-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxamide

The title compound was prepared following the same protocol as describedin Step 5, Example 34, using (S)-1-(4-bromophenyl)ethanamine instead ofthe 1-phenylpropan-1-amine. ESI-MS (m/z): 562/564 [M+H]⁺.

Example 36:1-((2′-(1H-Tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-N-(1-phenylpropyl)-1H-indole-5-carboxamide

To a solution of1-((2′-cyano-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-N-(1-phenylpropyl)-1H-indole-5-carboxamide(27 mg, 0.05 mmol, 1 equiv) in toluene (0.6 mL) in a high-pressure vialwere added TMSN₃ (14 μL, 0.05 mmol, 2 equiv) and Bu₂SnO (2 mg, 0.005mmol, 0.1 equiv). The vial was sealed and the reaction mixture washeated at reflux for 2 h. After concentration, the residue was purifiedby preparative HPLC to afford a beige powder. ESI-MS (m/z): 541 [M+H]⁺.

Example 37:(S)-1-((2′-(1H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-N-(1-(4-bromophenyl)ethyl)-2,3-dimethyl-1H-indole-5-carboxamide

The title compound was prepared following the same protocol as describedin Example 36, using(S)—N-(1-(4-bromophenyl)ethyl)-1-((2′-cyano-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxamideinstead of the1-((2′-cyano-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-N-(1-phenylpropyl)-1H-indole-5-carboxamide.ESI-MS (m/z): 605/607 [M+H]⁺.

Example 38:(S)-1-([1,1′-Biphenyl]-4-ylmethyl)-N-(1-(4-nitrophenyl)ethyl)-1H-indole-5-carboxamide

Step 1: Methyl 1H-indole-5-carboxylate

To a solution of 1H-indole-5-carboxylic acid (1 g, 6.2 mmol, 1.0 equiv)in acetonitrile (40 mL) were added 1,8-Diazabicyclo[5.4.0]undec-7-ene(1.1 mL, 7.4 mmol, 1.2 equiv) and iodomethane (2.3 mL, 37.2 mmol, 6equiv). The solution was stirred under reflux overnight. The reactionmixture was concentrated in vacuo. The residue was dissolved in AcOEt,washed with a 0.5 N HCl aqueous solution, a saturated NaHCO₃ solutionand brine, dried over MgSO₄ and concentrated in vacuo. The obtained oilwas used in the next step without further purification.

Step 2: Methyl 1-(4-bromobenzyl)-1H-indole-5-carboxylate

To a solution of methyl 1H-indole-5-carboxylate (1.09 g, 6.2 mmol, 1equiv) and 1-(bromomethyl)-4-bromobenzene (1.70 g, 6.82 mmol, 1.1 equiv)in anhydrous DMF (30 mL) under argon atmosphere was added sodium hydride(500 mg, 12.4 mmol, 2 equiv) in small portions. The mixture was stirred2 h at room temperature. The reaction mixture was then neutralized byaddition of methanol and concentrated in vacuo. The residue wasdissolved in AcOEt, washed with brine and dried over MgSO₄. The crudewas purified by flash chromatography (Hexane/AcOEt 7.5/2.5) to affordthe title compound as a white powder (1.09 g, 3.2 mmol, 52%). ESI-MS(m/z): 344/346 [M+H]⁺.

Step 3: 1-(4-Bromobenzyl)-1H-indole-5-carboxylic Acid

To a solution of methyl 1-(4-bromobenzyl)-1H-indole-5-carboxylate (1.09g, 3.2 mmol, 1 equiv) in methanol (30 mL) was added a 5 N NaOH solution(6.3 mL, 32 mmol, 10 equiv). The reaction mixture was stirred 2 h at 40°C. The mixture was then acidified and extracted with DCM. Afterconcentration in vacuo, the title compound was precipitated in Et₂O toafford a white powder (1.03 g, 3.1 mmol, 99%). ESI-MS (m/z): 330/332[M+H]⁺.

Step 4:(S)-1-(4-Bromobenzyl)-N-(1-(4-nitrophenyl)ethyl)-1H-indole-5-carboxamide

To a solution of 1-(4-bromobenzyl)-1H-indole-5-carboxylic acid (1.03 g,3.1 mmol, 1 equiv) in DMF (30 mL) were added the(S)-1-(4-nitrophenyl)ethanamine hydrochloride (695 mg, 3.4 mmol, 1.1equiv), DIEA (600 μL, 3.4 mmol, 1.1 equiv), HOBt (525 mg, 3.4 mmol, 1.1equiv) and EDC (658 mg, 3.4 mmol, 1.1 equiv). After stirring 4 h at roomtemperature, the mixture was diluted with AcOEt and washed with a 0.5 NHCl aqueous solution, a saturated NaHCO₃ solution and brine, dried overMgSO₄ and concentrated in vacuo. The crude was purified by flashchromatography (Hexane/AcOEt 1/1) to afford a yellow powder (1.3 g, 2.7mmol, 87%). ESI-MS (m/z): 478/480 [M+H]⁺.

Step 5:(S)-1-([1,1′-Biphenyl]-4-ylmethyl)-N-(1-(4-nitrophenyl)ethyl)-1H-indole-5-carboxamide

A high-pressure vial was filled with the(S)-1-(4-bromobenzyl)-N-(1-(4-nitrophenyl)ethyl)-1H-indole-5-carboxamide(50 mg, 0.1 mmol, 1 equiv), the phenylboronic acid (19 mg, 0.15 mmol,1.5 equiv), K₂CO₃ (29 mg, 0.2 mmol, 2 equiv), Pd(PPh₃)₄ (12 mg, 0.01mmol, 0.1 equiv), dioxane (1.5 mL) and water (0.3 mL). The mixture wasdegassed for 5 min under argon atmosphere and the vial was sealed. Thereaction mixture was heated at 100° C. for 30 min under microwaves. Thesolution was then concentrated in vacuo, filtered and purified bypreparative HPLC to afford a beige powder (50 mg, 0.1 mmol, 100%).ESI-MS (m/z): 476 [M+H]⁺.

Example 39:(S)-1-((2′-Methoxy-[1,1′-biphenyl]-4-yl)methyl)-N-(1-(4-nitrophenyl)ethyl)-1H-indole-5-carboxamide

The title compound was prepared following the same general protocol asdescribed in Step 5, Example 38, using (2-methoxyphenyl)boronic acidinstead of the phenylboronic acid. A yellow powder was obtained (32 mg,0.06 mmol, 61%). ESI-MS (m/z): 506 [M+H]⁺.

Example 40:(S)-1-((2′-Hydroxy-[1,1′-biphenyl]-4-yl)methyl)-N-(1-(4-nitrophenyl)ethyl)-1H-indole-5-carboxamide

The title compound was prepared following the same general protocol asdescribed in Step 5, Example 38, using (2-hydroxyphenyl)boronic acidinstead of the phenylboronic acid. A yellow powder was obtained (39 mg,0.08 mmol, 76%). ESI-MS (m/z): 492 [M+H]⁺.

Example 41:(S)-1-((2′-(Methylsulfonyl)-[1,1′-biphenyl]-4-yl)methyl)-N-(1-(4-nitrophenyl)ethyl)-1H-indole-5-carboxamide

The title compound was prepared following the same general protocol asdescribed in Step 5, Example 38, using (2-(methylsulfonyl)phenyl)boronicacid instead of the phenylboronic acid. A beige powder was obtained (46mg, 0.08 mmol, 80%). ESI-MS (m/z): 554 [M+H]⁺.

Example 42:(S)-1-((2′-Methyl-[1,1′-biphenyl]-4-yl)methyl)-N-(1-(4-nitrophenyl)ethyl)-1H-indole-5-carboxamide

The title compound was prepared following the same general protocol asdescribed in Step 5, Example 38, using o-tolylboronic acid instead ofthe phenylboronic acid. A yellow powder was obtained (35 mg, 0.07 mmol,69%). ESI-MS (m/z): 490 [M+H]⁺.

Example 43: (S)-Ethyl4′-((5-((1-(4-nitrophenyl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-4-carboxylate

The title compound was prepared following the same general protocol asdescribed in Step 5, Example 38, using (4-(ethoxycarbonyl)phenyl)boronicacid instead of the phenylboronic acid. A yellow powder was obtained (41mg, 0.07 mmol, 72%). ESI-MS (m/z): 548 [M+H]⁺.

Example 44:(S)-1-((3′-Methoxy-[1,1′-biphenyl]-4-yl)methyl)-N-(1-(4-nitrophenyl)ethyl)-1H-indole-5-carboxamide

The title compound was prepared following the same general protocol asdescribed in Step 5, Example 38, using (3-methoxyphenyl)boronic acidinstead of the phenylboronic acid. A yellow powder was obtained (44 mg,0.09 mmol, 84%). ESI-MS (m/z): 506 [M+H]⁺.

Example 45:(S)-1-((3′-(Methylsulfonyl)-[1,1′-biphenyl]-4-yl)methyl)-N-(1-(4-nitrophenyl)ethyl)-1H-indole-5-carboxamide

The title compound was prepared following the same general protocol asdescribed in Step 5, Example 38, using (3-(methylsulfonyl)phenyl)boronicacid instead of the phenylboronic acid. A yellow powder was obtained (49mg, 0.09 mmol, 85%). ESI-MS (m/z): 554 [M+H]⁺.

Example 46:(S)-1-((2′-Chloro-[1,1′-biphenyl]-4-yl)methyl)-N-(1-(4-nitrophenyl)ethyl)-1H-indole-5-carboxamide

The title compound was prepared following the same general protocol asdescribed in Step 5, Example 38, using (2-chlorophenyl)boronic acidinstead of the phenylboronic acid. A beige powder was obtained (39 mg,0.08 mmol, 74%). ESI-MS (m/z): 510 [M+H]⁺.

Example 47:(S)-1-((4′-Hydroxy-[1,1′-biphenyl]-4-yl)methyl)-N-(1-(4-nitrophenyl)ethyl)-1H-indole-5-carboxamide

The title compound was prepared following the same general protocol asdescribed in Step 5, Example 38, using (4-hydroxyphenyl)boronic acidinstead of the phenylboronic acid. A yellow powder was obtained (37 mg,0.08 mmol, 72%). ESI-MS (m/z): 492 [M+H]⁺.

Example 48: (S)-Ethyl4′-((5-((1-(4-nitrophenyl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-3-carboxylate

The title compound was prepared following the same general protocol asdescribed in Step 5, Example 38, using (3-(ethoxycarbonyl)phenyl)boronicacid instead of the phenylboronic acid. A yellow powder was obtained (48mg, 0.09 mmol, 84%). ESI-MS (m/z): 548 [M+H]⁺.

Example 49:(S)-1-((3′-Methyl-[1,1′-biphenyl]-4-yl)methyl)-N-(1-(4-nitrophenyl)ethyl)-1H-indole-5-carboxamide

The title compound was prepared following the same general protocol asdescribed in Step 5, Example 38, using m-tolylboronic acid instead ofthe phenylboronic acid. A yellow powder was obtained (38 mg, 0.08 mmol,75%). ESI-MS (m/z): 490 [M+H]⁺.

Example 50:(S)-1-((4′-(Methylsulfonyl)-[1,1′-biphenyl]-4-yl)methyl)-N-(1-(4-nitrophenyl)ethyl)-1H-indole-5-carboxamide

The title compound was prepared following the same general protocol asdescribed in Step 5, Example 38, using (4-(methylsulfonyl)phenyl)boronicacid instead of the phenylboronic acid. A beige powder was obtained (46mg, 0.08 mmol, 80%). ESI-MS (m/z): 554 [M+H]⁺.

Example 51:(S)-1-((4′-(Methylthio)-[1,1′-biphenyl]-4-yl)methyl)-N-(1-(4-nitrophenyl)ethyl)-1H-indole-5-carboxamide

The title compound was prepared following the same general protocol asdescribed in Step 5, Example 38, using (4-(methylthio)phenyl)boronicacid instead of the phenylboronic acid. A yellow powder was obtained (29mg, 0.06 mmol, 53%). ESI-MS (m/z): 522 [M+H]⁺.

Example 52:(S)-1-((3′-Amino-[1,1′-biphenyl]-4-yl)methyl)-N-(1-(4-nitrophenyl)ethyl)-1H-indole-5-carboxamide

The title compound was prepared following the same general protocol asdescribed in Step 5, Example 38, using (3-aminophenyl)boronic acidinstead of the phenylboronic acid. A beige powder was obtained (40 mg,0.08 mmol, 78%). ESI-MS (m/z): 491 [M+H]⁺.

Example 53:(S)-1-((3′-(Aminomethyl)-[1,1′-biphenyl]-4-yl)methyl)-N-(1-(4-nitrophenyl)ethyl)-1H-indole-5-carboxamide

The title compound was prepared following the same general protocol asdescribed in Step 5, Example 38, using (3-(aminomethyl)phenyl)boronicacid instead of the phenylboronic acid. A beige powder was obtained (47mg, 0.09 mmol, 90%). ESI-MS (m/z): 505 [M+H]⁺.

Example 54:(S)-1-((2′-(Hydroxymethyl)-[1,1′-biphenyl]-4-yl)methyl)-N-(1-(4-nitrophenyl)ethyl)-1H-indole-5-carboxamide

The title compound was prepared following the same general protocol asdescribed in Step 5, Example 38, using (2-(hydroxymethyl)phenyl)boronicacid instead of the phenylboronic acid. A beige powder was obtained (17mg, 0.03 mmol, 32%). ESI-MS (m/z): 506 [M+H]⁺.

Example 55: (S)-tert-Butyl4′-((5-((1-(4-nitrophenyl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylate

The title compound was prepared following the same general protocol asdescribed in Step 5, Example 38, using(2-(tert-butoxycarbonyl)phenyl)boronic acid instead of the phenylboronicacid. A yellow powder was obtained (47 mg, 0.08 mmol, 79%). ESI-MS(m/z): 576 [M+H]⁺.

Example 56: (S)-tert-Butyl4′-((5-((1-(4-nitrophenyl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-3-carboxylate

The title compound was prepared following the same general protocol asdescribed in Step 5, Example 38, using(3-(tert-butoxycarbonyl)phenyl)boronic acid instead of the phenylboronicacid. A yellow powder was obtained (43 mg, 0.07 mmol, 72%). ESI-MS(m/z): 576 [M+H]⁺.

Example 57:(S)-1-((4′-Methyl-[1,1′-biphenyl]-4-yl)methyl)-N-(1-(4-nitrophenyl)ethyl)-1H-indole-5-carboxamide

The title compound was prepared following the same general protocol asdescribed in Step 5, Example 38, using p-tolylboronic acid instead ofthe phenylboronic acid. A beige powder was obtained (13 mg, 0.03 mmol,26%). ESI-MS (m/z): 490 [M+H]⁺.

Example 58:(S)-1-((3′-Chloro-[1,1′-biphenyl]-4-yl)methyl)-N-(1-(4-nitrophenyl)ethyl)-1H-indole-5-carboxamide

The title compound was prepared following the same general protocol asdescribed in Step 5, Example 38, using (3-chlorophenyl)boronic acidinstead of the phenylboronic acid. A beige powder was obtained (18 mg,0.04 mmol, 34%). ESI-MS (m/z): 510 [M+H]⁺.

Example 59:(S)-4′-((5-((1-(4-Nitrophenyl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-4-carboxylicAcid

To a solution of (S)-ethyl4′-((5-((1-(4-nitrophenyl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-4-carboxylate(23 mg, 0.04 mmol, 1 equiv) in MeOH (1 mL) was added 100 μL of a 5 NNaOH solution. The mixture is stirred at room temperature overnight andthen hydrolyzed by addition of a 1 N HCl solution. After concentration,the crude is purified by preparative HPLC to afford a beige powder (9mg, 0.02 mmol, 43%). ESI-MS (m/z): 520 [M+H]⁺.

Example 60:(S)-4′-((5-((1-(4-Nitrophenyl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-3-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Example 59, using (S)-ethyl4′-((5-((1-(4-nitrophenyl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-3-carboxylateinstead of the (S)-ethyl4′-((5-((1-(4-nitrophenyl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-4-carboxylate.A beige powder was obtained (18 mg, 0.04 mmol, 34%). ESI-MS (m/z): 520[M+H]⁺.

Example 61:(S)-4′-((5-((1-(4-Nitrophenyl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

A solution of (S)-tert-butyl4′-((5-((1-(4-nitrophenyl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylate(23 mg, 0.04 mmol, 1 equiv) in DCM/TFA 1/1 was stirred for 30 min atroom temperature. The reaction mixture was neutralized by addition ofDIEA, concentrated and purified by preparative HPLC to afford a beigepowder (9 mg, 0.02 mmol, 43%). ESI-MS (m/z): 520 [M+H]⁺.

Example 62:(S)-2,3-Dimethyl-N-(1-(4-nitrophenyl)ethyl)-1-(4-(pyridin-3-yl)benzyl)-1H-indole-5-carboxamide

The title compound was prepared following the same general protocol asdescribed in Step 5, Example 38, using pyridin-3-ylboronic acid insteadof the phenylboronic acid. A beige powder was obtained (34 mg, 0.07mmol, 69%). ESI-MS (m/z): 477 [M+H]⁺.

Example 63:(S)-2,3-Dimethyl-N-(1-(4-nitrophenyl)ethyl)-1-(4-(pyridin-4-yl)benzyl)-1H-indole-5-carboxamide

The title compound was prepared following the same general protocol asdescribed in Step 5, Example 38, using pyridin-4-ylboronic acid insteadof the phenylboronic acid. A beige powder was obtained (37 mg, 0.08mmol, 75%).

ESI-MS (m/z): 477 [M+H]⁺

Example 64:(S)-2,3-Dimethyl-N-(1-(4-nitrophenyl)ethyl)-1-(4-(pyridin-2-yl)benzyl)-1H-indole-5-carboxamide

A high-pressure vial was filled with the(S)-1-(4-bromobenzyl)-N-(1-(4-nitrophenyl)ethyl)-1H-indole-5-carboxamide(37 mg, 0.08 mmol, 1 equiv), 2-(tributylstannyl)pyridine (28 μL, 0.09mmol, 1.1 equiv), LiCl (10 mg, 0.24 mmol, 3 equiv), Pd(PPh₃)₄ (9 mg,0.008 mmol, 0.1 equiv), and anhydrous DMF (1 mL). The mixture wasdegassed for 5 min under argon atmosphere and the vial was sealed. Thereaction mixture was heated at 120° C. for 1 h under microwaves. Thesolution was then concentrated in vacuo, filtered and purified bypreparative HPLC to afford a beige powder (18 mg, 0.4 mmol, 50%). ESI-MS(m/z): 477 [M+H]⁺.

Example 65:3′-((5-((1-phenylpropyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

Step 1: 1-(3-Bromobenzyl)-2,3-dimethyl-1H-indole-5-carboxylic Acid

The title compound is prepared following the same protocol as describedin Step 2, Example 38, using 1H-indole-5-carboxylic acid instead of themethyl 1H-indole-5-carboxylate, and 1-bromo-3-(bromomethyl)benzeneinstead of the 1-bromo-4-(bromomethyl)benzene. ESI-MS (m/z): 331 [M+H]⁺.

Step 2: 1-(3-Bromobenzyl)-N-(1-phenylpropyl)-1H-indole-5-carboxamide

The title compound was prepared following the same protocol as describedin Step 4, Example 38, using 1-phenylpropan-1-amine instead of the(S)-1-(4-nitrophenyl)ethanamine hydrochloride, and1-(2-Bromobenzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead ofthe 1-(4-bromobenzyl)-1H-indole-5-carboxylic acid. ESI-MS (m/z): 447/449[M+H]⁺.

Step 3: tert-Butyl3′-((5-((1-phenylpropyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylate

The title compound was prepared following the same protocol as describedin Example 55, using1-(3-Bromobenzyl)-N-(1-phenylpropyl)-1H-indole-5-carboxamide instead ofthe(S)-1-(4-bromobenzyl)-N-(1-(4-nitrophenyl)ethyl)-1H-indole-5-carboxamide.

Step 4:3′-((5-((1-Phenylpropyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same protocol as describedin Example 61, using tert-butyl3′-((5-((1-phenylpropyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylateinstead of the (S)-tert-butyl4′-((5-((1-(4-nitrophenyl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylate.ESI-MS (m/z): 489 [M+H]⁺.

Example 66:3′-((5-((1-Phenylpropyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-3-carboxylicAcid

Step 1: tert-Butyl3′-((5-((1-phenylpropyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-3-carboxylate

The title compound was prepared following the same protocol as describedin Example 56, using1-(3-Bromobenzyl)-N-(1-phenylpropyl)-1H-indole-5-carboxamide instead ofthe(S)-1-(4-bromobenzyl)-N-(1-(4-nitrophenyl)ethyl)-1H-indole-5-carboxamide.

Step 2:3′-((5-((1-Phenylpropyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-3-carboxylicAcid

The title compound was prepared following the same protocol as describedin Example 60, using tert-butyl3′-((5-((1-phenylpropyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-3-carboxylateinstead of the (S)-tert-butyl4′-((5-((1-(4-nitrophenyl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-3-carboxylate.ESI-MS (m/z): 489 [M+H]⁺.

Example 67:3′-((5-((1-Phenylpropyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-4-carboxylicAcid

Step 1: Ethyl3′-((5-((1-phenylpropyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-4-carboxylate

The title compound was prepared following the same protocol as describedin Example 43, using1-(3-Bromobenzyl)-N-(1-phenylpropyl)-1H-indole-5-carboxamide instead ofthe(S)-1-(4-bromobenzyl)-N-(1-(4-nitrophenyl)ethyl)-1H-indole-5-carboxamide.

Step 2:3′-((5-((1-Phenylpropyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-4-carboxylicAcid

The title compound was prepared following the same protocol as describedin Example 59, using ethyl3′-((5-((1-phenylpropyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-4-carboxylateinstead of the (S)-ethyl4′-((5-((1-(4-nitrophenyl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-4-carboxylate.ESI-MS (m/z): 489 [M+H]⁺.

Example 68:2′-((5-((1-phenylpropyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

Step 1: 1-(2-Bromobenzyl)-2,3-dimethyl-1H-indole-5-carboxylic Acid

The title compound was prepared following the same protocol as describedin Step 2, Example 38, using 1H-indole-5-carboxylic acid instead of themethyl 1H-indole-5-carboxylate, and 1-bromo-2-(bromomethyl)benzeneinstead of the 1-bromo-4-(bromomethyl)benzene.

ESI-MS (m/z): 331 [M+H]⁺.

Step 2: 1-(2-Bromobenzyl)-N-(1-phenylpropyl)-1H-indole-5-carboxamide

The title compound was prepared following the same protocol as describedin Step 4, Example 38, using 1-phenylpropan-1-amine instead of the(S)-1-(4-nitrophenyl)ethanamine hydrochloride, and1-(2-Bromobenzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead ofthe 1-(4-bromobenzyl)-1H-indole-5-carboxylic acid. ESI-MS (m/z): 447/449[M+H]⁺.

Step 3: tert-Butyl2′-((5-((1-phenylpropyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylate

The title compound was prepared following the same protocol as describedin Example 55, using1-(2-Bromobenzyl)-N-(1-phenylpropyl)-1H-indole-5-carboxamide instead ofthe(S)-1-(4-bromobenzyl)-N-(1-(4-nitrophenyl)ethyl)-1H-indole-5-carboxamide.

Step 4:2′-((5-((1-Phenylpropyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same protocol as describedin Example 61, using tert-butyl2′-((5-((1-phenylpropyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylateinstead of the (S)-tert-butyl4′-((5-((1-(4-nitrophenyl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylate.ESI-MS (m/z): 489 [M+H]⁺.

Example 69:2′-((5-((1-Phenylpropyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-3-carboxylicAcid

Step 1: tert-Butyl2′-((5-((1-phenylpropyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-3-carboxylate

The title compound was prepared following the same protocol as describedin Example 56, using1-(2-Bromobenzyl)-N-(1-phenylpropyl)-1H-indole-5-carboxamide instead ofthe(S)-1-(4-bromobenzyl)-N-(1-(4-nitrophenyl)ethyl)-1H-indole-5-carboxamide.

Step 2:2′-((5-((1-Phenylpropyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-3-carboxylicAcid

The title compound was prepared following the same protocol as describedin Example 60, using tert-butyl2′-((5-((1-phenylpropyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-3-carboxylateinstead of the (S)-tert-butyl4′-((5-((1-(4-nitrophenyl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-3-carboxylate.ESI-MS (m/z): 489 [M+H]⁺.

Example 70:2′-((5-((1-Phenylpropyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-4-carboxylicAcid

Step 1: Ethyl2′-((5-((1-phenylpropyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-4-carboxylate

The title compound was prepared following the same protocol as describedin Example 43, using1-(2-Bromobenzyl)-N-(1-phenylpropyl)-1H-indole-5-carboxamide instead ofthe(S)-1-(4-bromobenzyl)-N-(1-(4-nitrophenyl)ethyl)-1H-indole-5-carboxamide.

Step 2:2′-((5-((1-Phenylpropyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-4-carboxylicAcid

The title compound was prepared following the same protocol as describedin Example 59, using ethyl2′-((5-((1-phenylpropyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-4-carboxylateinstead of the (S)-ethyl4′-((5-((1-(4-nitrophenyl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-4-carboxylate.ESI-MS (m/z): 489 [M+H]⁺.

Example 72:(R)-4′-((2,3-dimethyl-5-(1-(4-nitrophenyl)ethylcarbamoyl)-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Steps 8-9, Example 1, using (R)-α-methyl-4-nitrobenzylamineand1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. LC-MS 548 (M+H).

Example 73:(S)-4′-((2,3-dimethyl-5-(1-(4-nitrophenyl)ethylcarbamoyl)-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Steps 8-9, Example 1, using (S)-α-methyl-4-nitrobenzylamineand1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. LC-MS 548 (M+H).

Example 74:(R)-4′-((2,3-dimethyl-5-(2-phenylpropylcarbamoyl)-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Steps 8-9, Example 1, using (R)-2-phenylpropan-1-amine and1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. LC-MS 517 (M+H).

Example 75:4′-((5-(benzhydrylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Steps 8-9, Example 1, using diphenylmethanamine and1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. LC-MS 515 (M+H).

Example 76:4′-((5-(4-fluorobenzylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Steps 8-9, Example 1, using 4-fluorobenzylamine and1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. LC-MS 507 (M+H).

Example 77:4′-((5-(3,4-difluorobenzylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Steps 8-9, Example 1, using 3,4-fluorobenzylamine and1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. LC-MS 524 (M+H).

Example 78:4′-((5-(benzo[d][1,3]dioxol-5-ylmethylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Steps 8-9, Example 1, usingbenzo[d][1,3]dioxol-5-ylmethanamine and1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. LC-MS 533 (M+H).

Example 79:(R)-4′-((5-(2-hydroxy-1-phenylethylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Steps 8-9, Example 1, using (R)-2-amino-2-phenylethanol and1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. LC-MS 519 (M+H).

Example 80:4′-((5-(3-aminobenzylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Steps 8-9, Example 1, using 3-aminobenzylamine and1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. LC-MS 504 (M+H).

Example 81:4′-((5-(cyclohexylmethylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Steps 8-9, Example 1, using cyclohexylmethylamine and1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. LC-MS 495 (M+H).

Example 82:4′-((5-(3-(aminomethyl)benzylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Steps 8-9, Example 1, using tert-butyl3-(aminomethyl)benzylcarbamate and1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. LC-MS 518 (M+H).

Example 83:4′-((2,3-dimethyl-5-(thiophen-2-ylmethylcarbamoyl)-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Steps 8-9, Example 1, using 2-thiophenemethylamine and1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. LC-MS 495 (M+H).

Example 84:4′-((2,3-dimethyl-5-((5-methylfuran-2-yl)methylcarbamoyl)-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Steps 8-9, Example 1, using 5-methyl-2-furanylmethylamineand1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. LC-MS 493 (M+H).

Example 85:4′-((2,3-dimethyl-5-(2-morpholinoethylcarbamoyl)-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Steps 8-9, Example 1, using 2-morphorinethylamine and1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. LC-MS 512 (M+H).

Example 86:4′-((5-(chroman-3-ylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Steps 8-9, Example 1, using chroman-3-amine and1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. LC-MS 531 (M+H).

Example 87:4′-((5-(chroman-3-ylmethylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Steps 8-9, Example 1, using chroman-3-ylmethanamine and1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. LC-MS 545 (M+H).

Example 88:4′-((5-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Steps 8-9, Example 1, using(2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methanamine and1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. LC-MS 547 (M+H).

Example 89:4′-((5-(cyclobutylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Steps 8-9, Example 1, using cyclobutylamine and1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. LC-MS 453 (M+H).

Example 90:4′-((5-(cyclopentylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Steps 8-9, Example 1, using cyclopentylamine and1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. LC-MS 467 (M+H).

Example 91:4′-((5-(3-aminocyclohexylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Steps 8-9, Example 1, using tert-butyl3-aminocyclohexylcarbamate and1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. LC-MS 496 (M+H).

Example 92:4′-((5-(2-methoxyethylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Steps 8-9, Example 1, using 2-methoxyethyleneamine and1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. LC-MS 457 (M+H).

Example 93:4′-((5-(benzylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Steps 8-9, Example 1, using benzylamine and1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. LC-MS 489 (M+H).

Example 94:4′-((5-(2-aminobenzylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Steps 8-9, Example 1, using 2-aminobenzylamine and1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. LC-MS 504 (M+H).

Example 95:4′-((5-(4-aminobenzylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Steps 8-9, Example 1, using 4-aminobenzylamine and1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. LC-MS 504 (M+H).

Example 96:4′-((2,3-dimethyl-5-(4-nitrobenzylcarbamoyl)-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Steps 8-9, Example 1, using 4-nitrobenzylamine and1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. LC-MS 534 (M+H).

Example 97:(R)-4′-((2,3-dimethyl-5-(1-phenylpropylcarbamoyl)-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Steps 8-9, Example 1, using (R)-a-ethylbenzylamine and1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. LC-MS 517 (M+H).

Example 98:(S)-4′-((2,3-dimethyl-5-(1-phenylpropylcarbamoyl)-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Steps 8-9, Example 1, using (S)-a-ethylbenzylamine and1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. LC-MS 517 (M+H).

Example 99:(S)-4′-((5-(1-(4-aminophenyl)ethylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Steps 8-9, Example 1, using 4-amino-(S)-a-methylbenzylamineand1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. LC-MS 518 (M+H).

Example 100:4′-((2,3-dimethyl-5-(3-(trifluoromethyl)benzylcarbamoyl)-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Steps 8-9, Example 1, using 3-trifluoromethylbenzylamineand1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. LC-MS 557 (M+H).

Example 101:4′-((2,3-dimethyl-5-(4-(trifluoromethyl)benzylcarbamoyl)-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Steps 8-9, Example 1, using 4-trifluoromethylbenzylamineand1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. LC-MS 557 (M+H).

Example 102:4′-((5-(biphenyl-4-ylmethylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Steps 8-9, Example 1, using 4-phenylbenzylamine and1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. LC-MS 565 (M+H).

Example 103:4′-((5-(3-methoxybenzylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Steps 8-9, Example 1, using 3-methoxylbenzylamine and1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. LC-MS 519 (M+H).

Example 104:4′-((5-(4-methoxybenzylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Steps 8-9, Example 1, using 4-methoxylbenzylamine and1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. LC-MS 519 (M+H).

Example 105:4′-((2,3-dimethyl-5-(3-methylbenzylcarbamoyl)-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Steps 8-9, Example 1, using 3-methylbenzylamine and1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. LC-MS 503 (M+H).

Example 106:4′-((2,3-dimethyl-5-(4-methylbenzylcarbamoyl)-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Steps 8-9, Example 1, using 4-methylbenzylamine and1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. LC-MS 503 (M+H).

Example 107:4′-((2,3-dimethyl-5-(2-methylbenzylcarbamoyl)-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Steps 8-9, Example 1, using 2-methylbenzylamine and1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. LC-MS 503 (M+H).

Example 108:4′-((5-(2-chlorobenzylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Steps 8-9, Example 1, using 2-chlorobenzylamine and1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. LC-MS 523 (M+H).

Example 109:4′-((5-(3-chlorobenzylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Steps 8-9, Example 1, using 3-chlorobenzylamine and1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. LC-MS 523 (M+H).

Example 110:4′-((2,3-dimethyl-5-(3-nitrobenzylcarbamoyl)-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Steps 8-9, Example 1, using 3-nitrobenzylamine and1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. LC-MS 534 (M+H).

Example 111:4′-((5-(3-fluoro-4-methoxybenzylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Steps 8-9, Example 1, using 3-fluoro-4-methoxybenzylamineand1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. LC-MS 537 (M+H).

Example 112:(S)-4′-((5-(1-(4-fluorophenyl)ethylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Steps 8-9, Example 1, using4-fluoro-a-(S)-methylbenzylamine and1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. LC-MS 521 (M+H).

Example 113:(R)-4′-((5-(1-(4-fluorophenyl)ethylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Steps 8-9, Example 1, using4-fluoro-a-(R)-methylbenzylamine and1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. LC-MS 521 (M+H).

Example 114:(S)-4′-((2,3-dimethyl-5-(1-phenylbutylcarbamoyl)-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Steps 8-9, Example 1, using a-(S)-ethylbenzylamine and1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. LC-MS 531 (M+H).

Example 115:4′-((2,3-dimethyl-5-(naphthalen-1-ylmethylcarbamoyl)-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Steps 8-9, Example 1, using 1-naphthylmethylamine and1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. LC-MS 539 (M+H).

Example 116:4′-((2,3-dimethyl-5-(1-(naphthalen-1-yl)ethylcarbamoyl)-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Steps 8-9, Example 1, using 1-(naphthalen-1-yl)ethanamineand1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. LC-MS 553 (M+H).

Example 117:4′-((2,3-dimethyl-5-(4-phenylbutan-2-ylcarbamoyl)-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Steps 8-9, Example 1, using 4-phenylbutan-2-amine and1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. LC-MS 531 (M+H).

Example 118:4′-((5-((2-Bromobenzyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

Step 1: tert-Butyl4′-((5-((2-bromobenzyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylate

The title compound was prepared following the same general protocol asdescribed in Step 8, Example 1, the (2-bromophenyl)methanamine was usedinstead of the (S)-1-(4-bromophenyl)ethanamine.

ESI-MS (m/z): 623/625 [M+H]⁺.

Step 2:4′-((5-(2-Bromobenzyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 9, Example 1.

ESI-MS (m/z): 567/569 [M+H]⁺.

Example 119:4′-((5-((2-Nitrobenzyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

Step 1: tert-Butyl4′-((5-((2-nitrobenzyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylate

The title compound was prepared following the same general protocol asdescribed in Step 8, Example 1, the (2-nitrophenyl)methanamine was usedinstead of the (S)-1-(4-bromophenyl)ethanamine.

ESI-MS (m/z): 590 [M+H]⁺.

Step 2:4′4542-Nitrobenzyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 9, Example 1.

ESI-MS (m/z): 534 [M+H]⁺.

Example 120:(S)-2′-((5-((1-(4-Bromophenyl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-4-carboxylicAcid

Step 1: 1-(3-Bromobenzyl)-2,3-dimethyl-1H-indole-5-carboxylic Acid

The title compound was prepared following the same protocol as describedin Step 2, Example 38, using 1H-indole-5-carboxylic acid instead of themethyl 1H-indole-5-carboxylate, and 1-bromo-2-(bromomethyl)benzeneinstead of the 1-bromo-4-(bromomethyl)benzene. ESI-MS (m/z): 330/332[M+H]⁺.

Step 2:1-((4′-(Ethoxycarbonyl)-[1,1′-biphenyl]-2-yl)methyl)-1H-indole-5-carboxylicAcid

The title compound was prepared following the same protocol as describedin Step 5, Example 38, using 1-(2-bromobenzyl)-1H-indole-5-carboxylicacid instead of the(S)-1-(4-bromobenzyl)-N-(1-(4-nitrophenyl)ethyl)-1H-indole-5-carboxamideand the (4-(ethoxycarbonyl)phenyl)boronic acid instead of thephenylboronic acid. ESI-MS (m/z): 400 [M+H]⁺.

Step 3: (S)-Ethyl2′-((5-((1-(4-bromophenyl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-4-carboxylate

The title compound was prepared following the same protocol as describedin Step 8, Example 1, using the1-((4′-(ethoxycarbonyl)-[1,1′-biphenyl]-2-yl)methyl)-1H-indole-5-carboxylicacid instead of the1-((2′-(tert-Butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid.

Step 4:(S)-2′-((5-((1-(4-Bromophenyl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-4-carboxylicAcid

The title compound was prepared following the same protocol as describedin Example 59, using (S)-ethyl2′-((5-((1-(4-bromophenyl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-4-carboxylateinstead of the (S)-ethyl4′-((5-((1-(4-nitrophenyl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-4-carboxylate.ESI-MS (m/z): 553/555 [M+H]⁺.

Example 121:(S)-2′-((5-((1-(4-Nitrophenyl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-4-carboxylicAcid

Step 1: (S)-Ethyl2′-((5-((1-(4-nitrophenyl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-4-carboxylate

The title compound was prepared following the same protocol as describedin Step 8, Example 1, using the1-((4′-(ethoxycarbonyl)-[1,1′-biphenyl]-2-yl)methyl)-1H-indole-5-carboxylicacid instead of the1-((2′-(tert-Butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid and the (S)-1-(4-nitrophenyl)ethanamine instead of the(S)-1-(4-bromophenyl)ethanamine.

Step 2:(S)-2′-((5-((1-(4-Nitrophenyl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-4-carboxylicAcid

The title compound was prepared following the same protocol as describedin Example 59, using (S)-ethyl2′-((5-((1-(4-nitrophenyl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-4-carboxylateinstead of the (S)-ethyl4′-((5-((1-(4-nitrophenyl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-4-carboxylate.ESI-MS (m/z): 520 [M+H]⁺.

Example 122:(S)-2′-((5-((1-(4-Bromophenyl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-3-carboxylicAcid

Step 1:1-((3′-(Ethoxycarbonyl)-[1,1′-biphenyl]-2-yl)methyl)-1H-indole-5-carboxylicAcid

The title compound was prepared following the same protocol as describedin Step 5, Example 38, using 1-(2-bromobenzyl)-1H-indole-5-carboxylicacid instead of the(S)-1-(4-bromobenzyl)-N-(1-(4-nitrophenyl)ethyl)-1H-indole-5-carboxamideand the (3-(ethoxycarbonyl)phenyl)boronic acid instead of thephenylboronic acid. ESI-MS (m/z): 400 [M+H]⁺.

Step 2: (S)-Ethyl2′-((5-((1-(4-bromophenyl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-3-carboxylate

The title compound was prepared following the same protocol as describedin Step 8, Example 1, using the1-((3′-(ethoxycarbonyl)-[1,1′-biphenyl]-2-yl)methyl)-1H-indole-5-carboxylicacid instead of the1-((2′-(tert-Butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid.

Step 3:(S)-2′-((5-((1-(4-Bromophenyl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-3-carboxylicAcid

The title compound was prepared following the same protocol as describedin Example 59, using (S)-ethyl2′-((5-((1-(4-bromophenyl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-3-carboxylateinstead of the (S)-ethyl4′-((5-((1-(4-nitrophenyl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-4-carboxylate.ESI-MS (m/z): 553/555 [M+H]⁺.

Example 123:(S)-2′-((5-((1-(4-Nitrophenyl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-3-carboxylicAcid

Step 1: (S)-Ethyl2′-((5-((1-(4-nitrophenyl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-3-carboxylate

The title compound was prepared following the same protocol as describedin Step 8, Example 1, using the1-((3′-(ethoxycarbonyl)-[1,1′-biphenyl]-2-yl)methyl)-1H-indole-5-carboxylicacid instead of the1-((2′-(tert-Butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid and the (S)-1-(4-nitrophenyl)ethanamine instead of the(S)-1-(4-bromophenyl)ethanamine.

Step 2:(S)-2′-((5-((1-(4-Nitrophenyl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-3-carboxylicAcid

The title compound was prepared following the same protocol as describedin Example 59, using (S)-ethyl2′-((5-((1-(4-nitrophenyl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-3-carboxylateinstead of the (S)-ethyl4′-((5-((1-(4-nitrophenyl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-4-carboxylate.ESI-MS (m/z): 520 [M+H]⁺.

Example 124:(S)-2′-((5-((1-(4-Bromophenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-3-carboxylicAcid

Step 1: Ethyl 1-(2-bromobenzyl)-2,3-dimethyl-1H-indole-5-carboxylate

The title compound was prepared following the same protocol as describedin Step 6, Example 1, using the 1-bromo-2-(bromomethyl)benzene insteadof the tert-butyl 4′-(bromomethyl)biphenyl-2-carboxylate. ESI-MS (m/z):386/388 [M+H]⁺.

Step 2: 1-(2-Bromobenzyl)-2,3-dimethyl-1H-indole-5-carboxylic Acid

The title compound was prepared following the same protocol as describedin Step 7, Example 1, using the ethyl1-(2-bromobenzyl)-2,3-dimethyl-1H-indole-5-carboxylate instead of theethyl1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylate.ESI-MS (m/z): 358/360 [M+H]⁺.

Step 3:1-((3′-(Ethoxycarbonyl)-[1,1′-biphenyl]-2-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicAcid

The title compound was prepared following the same protocol as describedin Step 5, Example 38, using1-(2-bromobenzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead ofthe(S)-1-(4-bromobenzyl)-N-(1-(4-nitrophenyl)ethyl)-1H-indole-5-carboxamideand the (3-(ethoxycarbonyl)phenyl)boronic acid instead of thephenylboronic acid. ESI-MS (m/z): 428 [M+H]⁺.

Step 4: (S)-Ethyl2′-((5-((1-(4-bromophenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-3-carboxylate

The title compound was prepared following the same protocol as describedin Step 8, Example 1, using the1-((3′-(ethoxycarbonyl)-[1,1′-biphenyl]-2-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid instead of the1-((2′-(tert-Butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid.

Step 5:(S)-2′-((5-((1-(4-Bromophenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-3-carboxylicAcid

The title compound was prepared following the same protocol as describedin Example 59, using (S)-ethyl2′-((5-((1-(4-bromophenyl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-3-carboxylateinstead of the (S)-ethyl4′-((5-((1-(4-nitrophenyl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-4-carboxylate.ESI-MS (m/z): 581/583 [M+H]⁺.

Example 125:(S)-2′-((2,3-Dimethyl-5-((1-(4-nitrophenyl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-3-carboxylicAcid

Step 1: (S)-Ethyl2′-((2,3-dimethyl-5-((1-(4-nitrophenyl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-3-carboxylate

The title compound was prepared following the same protocol as describedin Step 8, Example 1, using the1-((3′-(ethoxycarbonyl)-[1,1′-biphenyl]-2-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid instead of the1-((2′-(tert-Butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid and the (S)-1-(4-nitrophenyl)ethanamine instead of the(S)-1-(4-bromophenyl)ethanamine.

Step 2:(S)-2′-((2,3-Dimethyl-5-((1-(4-nitrophenyl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-3-carboxylicAcid

The title compound was prepared following the same protocol as describedin Example 59, using (S)-ethyl2′-((2,3-dimethyl-5-((1-(4-nitrophenyl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-3-carboxylateinstead of the (S)-ethyl4′-((5-((1-(4-nitrophenyl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-4-carboxylate.ESI-MS (m/z): 548 [M+H]⁺.

Example 126:2′-((2,3-Dimethyl-5-((1-phenylpropyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-3-carboxylicAcid

Step 1: Ethyl2′-((2,3-dimethyl-5-((1-phenylpropyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-3-carboxylate

The title compound was prepared following the same protocol as describedin Step 8, Example 1, using the1-((3′-(ethoxycarbonyl)-[1,1′-biphenyl]-2-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid instead of the1-((2′-(tert-Butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid and the 1-phenylpropan-1-amine instead of the(S)-1-(4-bromophenyl)ethanamine.

Step 2:2′-((2,3-Dimethyl-5-((1-phenylpropyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-3-carboxylicAcid

The title compound was prepared following the same protocol as describedin Example 59, using ethyl2′-((2,3-dimethyl-5-((1-phenylpropyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-3-carboxylateinstead of the (S)-ethyl4′-((5-((1-(4-nitrophenyl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-4-carboxylate.ESI-MS (m/z): 517 [M+H]⁺.

Example 127:(S)-2′-((5-((1-(4-bromophenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-4-carboxylicAcid

Step 1:1-((4′-(Ethoxycarbonyl)-[1,1′-biphenyl]-2-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicAcid

The title compound was prepared following the same protocol as describedin Step 5, Example 38, using1-(2-bromobenzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead ofthe(S)-1-(4-bromobenzyl)-N-(1-(4-nitrophenyl)ethyl)-1H-indole-5-carboxamideand the (4-(ethoxycarbonyl)phenyl)boronic acid instead of thephenylboronic acid. ESI-MS (m/z): 428 [M+H]⁺.

Step 2: (S)-Ethyl2′-((5-((1-(4-bromophenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-4-carboxylate

The title compound was prepared following the same protocol as describedin Step 8, Example 1, using the1-((4′-(ethoxycarbonyl)-[1,1′-biphenyl]-2-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid instead of the1-((2′-(tert-Butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid.

Step 3:(S)-2′-((5-((1-(4-Bromophenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-4-carboxylicAcid

The title compound was prepared following the same protocol as describedin Example 59, using (S)-ethyl2′-((5-((1-(4-bromophenyl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-4-carboxylateinstead of the (S)-ethyl4′-((5-((1-(4-nitrophenyl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-4-carboxylate.ESI-MS (m/z): 581/583 [M+H]⁺.

Example 128:(S)-2′-((2,3-Dimethyl-5-((1-(4-nitrophenyl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-4-carboxylicAcid

Step 1: (S)-Ethyl2′-((2,3-dimethyl-5-((1-(4-nitrophenyl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-4-carboxylate

The title compound was prepared following the same protocol as describedin Step 8, Example 1, using the1-((4′-(ethoxycarbonyl)-[1,1′-biphenyl]-2-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid instead of the1-((2′-(tert-Butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid and the (S)-1-(4-nitrophenyl)ethanamine instead of the(S)-1-(4-bromophenyl)ethanamine.

Step 2:(S)-2′-((2,3-Dimethyl-5-((1-(4-nitrophenyl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-4-carboxylicAcid

The title compound was prepared following the same protocol as describedin Example 59, using (S)-ethyl2′-((2,3-dimethyl-5-((1-(4-nitrophenyl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-4-carboxylateinstead of the (S)-ethyl4′-((5-((1-(4-nitrophenyl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-4-carboxylate.ESI-MS (m/z): 548 [M+H]⁺.

Example 129:2′-((2,3-Dimethyl-5-((1-phenylpropyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-4-carboxylicAcid

Step 1: Ethyl2′-((2,3-dimethyl-5-((1-phenylpropyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-4-carboxylate

The title compound was prepared following the same protocol as describedin Step 8, Example 1, using the1-((4′-(ethoxycarbonyl)-[1,1′-biphenyl]-2-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid instead of the1-((2′-(tert-Butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid and the 1-phenylpropan-1-amine instead of the(S)-1-(4-bromophenyl)ethanamine.

Step 2:2′-((2,3-Dimethyl-5-((1-phenylpropyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-4-carboxylicAcid

The title compound was prepared following the same protocol as describedin Example 59, using ethyl2′-((2,3-dimethyl-5-((1-phenylpropyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-4-carboxylateinstead of the (S)-ethyl4′-((5-((1-(4-nitrophenyl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-4-carboxylate.ESI-MS (m/z): 517 [M+H]⁺.

Example 130:(S)-4′-((5-((1-(4-Bromophenyl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

Step 1:1-((2′-(tert-Butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-1H-indole-5-carboxylicAcid

The title compound was prepared following the same protocol as describedin Step 2, Example 38, using 1H-indole-5-carboxylic acid instead of themethyl 1H-indole-5-carboxylate, and the tert-butyl4′-(bromomethyl)biphenyl-2-carboxylate instead of the1-bromo-4-(bromomethyl)benzene. ESI-MS (m/z): 428 [M+H]⁺.

Step 2: (S)-tert-Butyl4′-((5-((1-(4-bromophenyl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylate

The title compound was prepared following the same protocol as describedin Step 8, Example 1, using the1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-1H-indole-5-carboxylicacid instead of the1-((2′-(tert-Butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid.

Step 3:(S)-4′-((5-((1-(4-Bromophenyl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same protocol as describedin Step 9, Example 1, using (S)-tert-Butyl4′-((5-((1-(4-bromophenyl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylateinstead of the (S)-tert-Butyl4′-((5-((1-(4-bromophenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylate.ESI-MS (m/z): 553/555 [M+H]⁺.

Example 131:4′-((5-((1-Phenylpropyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

Step 1: tert-Butyl4′-((5-((1-phenylpropyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylate

The title compound was prepared following the same protocol as describedin Step 8, Example 1, using the1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-1H-indole-5-carboxylicacid instead of the1-((2′-(tert-Butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid and the 1-phenylpropan-1-amine instead of the(S)-1-(4-bromophenyl)ethanamine.

Step 2:4′-((5-((1-Phenylpropyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same protocol as describedin Step 9, Example 1, using tert-butyl4′-((5-((1-phenylpropyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylateinstead of the (S)-tert-butyl4′-((5-((1-(4-bromophenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylate.ESI-MS (m/z): 489 [M+H]⁺.

Example 132:(S)-4′-((5-((1-(4-Bromophenyl)ethyl)carbamoyl)-3-methyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

Step 1: Methyl 3-formyl-1H-indole-5-carboxylate

To a solution of anhydrous DMF (12 mL) under argon at 0° C. was addedPOCl₃ (446 μL, 4.9 mmol). The reaction mixture has been stirred at 0° C.for 5 min. The methyl 1H-indole-5-carboxylate (854 mg, 4.9 mmol) insolution in DMF was added dropwise. The resulting mixture has beenheated at 120° C. for 1 h. Then, it is quenched by addition of asaturated solution of NaHCO₃ (2 mL). The mixture is diluted with DCM,washed with brine, dried over MgSO₄ and concentrated. The product isprecipitated in hexane/diethyl ether (1/1) to yield a red powder (896mg, 4.4 mmol, 91%). ESI-MS (m/z): 204 [M+H]⁺.

Step 2: Methyl 3-methyl-1H-indole-5-carboxylate

To a solution of the methyl 3-formyl-1H-indole-5-carboxylate (893 mg,4.4 mmol) in DMF (20 mL) was added the p-toluenesulfonic acidmonohydrate (125 mg, 0.7 mmol) and the p-toluenesulfonyl hydrazide (982mg, 5.3 mmol). The solution has been heated for 20 min at 100° C. Theresulting mixture was diluted with ethyl acetate, washed with brine,dried over MgSO₄ and concentrated. The crude product is dissolved in THF(40 mL) and NaBH₃CN (1.1 g, 17.6 mmol) was added. The solution has beenheated for 8 h at 75° C. The resulting mixture was diluted with ethylacetate, washed with a solution of 0.5 N HCl, a saturated solution ofNaHCO₃ and brine, dried over MgSO₄ and concentrated. The crude productwas purified by flash chromatography (Hexane/AcOEt, from 0 to 30%) toyield a white powder (500 mg, 2.6 mmol, 60%). ESI-MS (m/z): 190 [M+H]⁺.

Step 3: Methyl1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-3-methyl-1H-indole-5-carboxylate

The title compound was prepared following the same protocol as describedin Step 2, Example 38, using the methyl 3-methyl-1H-indole-5-carboxylateinstead of the methyl 1H-indole-5-carboxylate, and the tert-butyl4′-(bromomethyl)biphenyl-2-carboxylate instead of the1-bromo-4-(bromomethyl)benzene. ESI-MS (m/z): 456 [M+H]⁺.

Step 4:1-((2′-(tert-Butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-3-methyl-1H-indole-5-carboxylicAcid

The title compound was prepared following the same protocol as describedin Step 3, Example 38, using the methyl1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-3-methyl-1H-indole-5-carboxylateinstead of the methyl 1-(4-bromobenzyl)-1H-indole-5-carboxylate. ESI-MS(m/z): 442 [M+H]⁺.

Step 5: (S)-tert-Butyl4′-((5-((1-(4-bromophenyl)ethyl)carbamoyl)-3-methyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylate

The title compound was prepared following the same protocol as describedin Step 8, Example 1, using the1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-3-methyl-1H-indole-5-carboxylicacid instead of the1-((2′-(tert-Butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid.

Step 6:(S)-4′-((5-((1-(4-Bromophenyl)ethyl)carbamoyl)-3-methyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same protocol as describedin Step 9, Example 1, using the (S)-tert-Butyl4′-((5-((1-(4-bromophenyl)ethyl)carbamoyl)-3-methyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylateinstead of the (S)-tert-Butyl4′-((5-((1-(4-bromophenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylate.ESI-MS (m/z): 566/568 [M+H]⁺.

Example 133:4′-((3-Methyl-5-((1-phenylpropyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

Step 1: tert-Butyl4′-((3-methyl-5-(1-phenylpropyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylate

The title compound was prepared following the same protocol as describedin Step 8, Example 1, using the1-((2′-(tert-Butoxycarbonyl)biphenyl-4-yl)methyl)-3-methyl-1H-indole-5-carboxylicacid instead of the1-((2′-(tert-Butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid and the 1-phenylpropan-1-amine instead of the(S)-1-(4-bromophenyl)ethanamine.

Step 2:4′-((3-Methyl-5-((1-phenylpropyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same protocol as describedin Step 9, Example 1, using the tert-Butyl4′-((3-methyl-5-((1-phenylpropyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylateinstead of the (S)-tert-butyl4′-((5-((1-(4-bromophenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylate.ESI-MS (m/z): 559 [M+H]⁺.

Example 134:(S)-4′-((3-Methyl-5-((1-(4-nitrophenyl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

Step 1: (S)-tert-Butyl4′-((5-((1-(4-nitrophenyl)ethyl)carbamoyl)-3-methyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylate

The title compound was prepared following the same protocol as describedin Step 8, Example 1, using the1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-3-methyl-1H-indole-5-carboxylicacid instead of the1-((2′-(tert-Butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid and the (S)-1-(4-nitrophenyl)ethanamine instead of the(S)-1-(4-bromophenyl)ethanamine.

Step 2:(S)-4′-((3-methyl-5-((1-(4-nitrophenyl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same protocol as describedin Step 9, Example 1, using the (S)-tert-Butyl4′-((5-((1-(4-nitrophenyl)ethyl)carbamoyl)-3-methyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylateinstead of the (S)-tert-Butyl4′-((5-((1-(4-bromophenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylate.ESI-MS (m/z): 533 [M+H]⁺.

Example 135:(S)-4′-((5-((1-(4-Bromophenyl)ethyl)carbamoyl)-2-methyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

Step 1: Methyl1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2-methyl-1H-indole-5-carboxylate

The title compound was prepared following the same protocol as describedin Step 2, Example 38, using the methyl 2-methyl-1H-indole-5-carboxylateinstead of the methyl 1H-indole-5-carboxylate, and the tert-butyl4′-(bromomethyl)biphenyl-2-carboxylate instead of the1-bromo-4-(bromomethyl)benzene. ESI-MS (m/z): 456 [M+H]⁺.

Step 2:1-((2′-(tert-Butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2-methyl-1H-indole-5-carboxylicAcid

The title compound was prepared following the same protocol as describedin Step 3, Example 38, using the methyl1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2-methyl-1H-indole-5-carboxylateinstead of the methyl 1-(4-bromobenzyl)-1H-indole-5-carboxylate. ESI-MS(m/z): 442 [M+H]⁺.

Step 3: (S)-tert-Butyl4′-((5-((1-(4-bromophenyl)ethyl)carbamoyl)-2-methyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylate

The title compound was prepared following the same protocol as describedin Step 8, Example 1, using the1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2-methyl-1H-indole-5-carboxylicacid instead of the1-((2′-(tert-Butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid.

Step 4:(S)-4′-((5-((1-(4-Bromophenyl)ethyl)carbamoyl)-2-methyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same protocol as describedin Step 9, Example 1, using the (S)-tert-Butyl4′-((5-((1-(4-bromophenyl)ethyl)carbamoyl)-2-methyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylateinstead of the (S)-tert-Butyl4′-((5-((1-(4-bromophenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylate.ESI-MS (m/z): 566/568 [M+H]⁺.

Example 136:4′-((2-Methyl-5-((1-phenylpropyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

Step 1: tert-Butyl4′-((2-methyl-5-((1-phenylpropyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylate

The title compound was prepared following the same protocol as describedin Step 8, Example 1, using the1-((2′-(tert-Butoxycarbonyl)biphenyl-4-yl)methyl)-2-methyl-1H-indole-5-carboxylicacid instead of the1-((2′-(tert-Butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid and the 1-phenylpropan-1-amine instead of the(S)-1-(4-bromophenyl)ethanamine.

Step 2:4′42-Methyl-5-((1-phenylpropyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same protocol as describedin Step 9, Example 1, using the tert-Butyl4′-((2-methyl-5-((1-phenylpropyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylateinstead of the (S)-tert-butyl4′-((5-((1-((4-bromophenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylate.ESI-MS (m/z): 559 [M+H]⁺.

Example 137:(S)-4′-((5-((1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

Step 1: (S)-tert-butyl4′-((2,3-dimethyl-5-((1-(3-(prop-1-en-2-yl)phenyl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylate

A solution of (S)-tert-butyl4′-((5-((1-(3-bromophenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylate(83 mg, 0.13 mmol, 1 equiv.), K₂CO₃ (36 mg, 0.26 mmol, 2 equiv.) andPd(PPh₃)₄ (15 mg, 0.013 mmol, 0.1 equiv.) in dioxane/water (1.2 mL/0.3mL) was degassed with argon. The isopropenylboronic acid pinacol ester(49 μL, 0.26 mmol, 2 equiv.) was added and the solution was heated at100° C. for 1 h under microwave irradiation. The resulting solution wasdiluted with ethyl acetate, washed with a 0.5 N HCl solution, saturatedaqueous NaHCO₃ and brine, and then dried over Na₂SO₄. The obtained oilwas used without further purification. ESI-MS (m/z): 599 [M+H]⁺.

Step 2: (S)-tert-butyl4′-((5-((1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylate

A solution of (S)-tert-butyl4′-((2,3-dimethyl-5-((1-(3-(prop-1-en-2-yl)phenyl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylate(0.13 mmol, 1 equiv.) in ethanol (5 mL) was degassed with argon. A hintof Pd/C 10% was added to the solution. The suspension was stirred at rtfor 5 h under H₂ bubbling. The resulting mixture was then filtered andconcentrated. The obtained oil was used without further purification.ESI-MS (m/z): 601 [M+H]⁺.

Step 3:(S)-4′-((5-((1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 9, Example 1. ESI-MS (m/z): 545 [M+H]⁺.

Example 138:(S)-4′-((5-((1-(3-(tert-butyl)phenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

Step 1: (S)-1-(3-(tert-butyl)phenyl)ethanaminium Chloride

The title compound was prepared following the same general syntheticprocedure as described in Steps 1-2, Example 2, using3-(tert-butyl)benzaldehyde instead of 4-(tert-butyl)benzaldehyde.

Step 2:(S)-4′-((5-((1-(3-(tert-butyl)phenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 8-9, Example 1, using(S)-1-(3-(tert-butyl)phenyl)ethanamine and1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. ESI-MS (m/z): 559 [M+H]⁺.

Example 139:(R)-4′-((2,3-dimethyl-5-((2,2,2-trifluoro-1-(3-isopropylphenyl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

Step 1: (S,E)-N-(3-isopropylbenzylidene)-2-methylpropane-2-sulfinamide

To a solution of 3-isopropylbenzaldehyde (0.711 g, 4.75 mmol) in THF (5mL) was added (S)-2-methyl-2-propanesulfinamide (0.534 g, 4.32 mmol) andTi(OiPr)₄ (2.75 mL, 8.64 mmol). The resulting mixture was allowed tostir over night at rt where it was then quenched with aqueous NH₄Cl (5mL) and diluted with EtOAc (100 mL). The mixture was then filteredthrough celite using excess EtOAc to rinse, concentrated to an oil crudeand separated by silica gel (EtOAc:Hexanes) to isolate the titlecompound.

Step 2:(S)-2-methyl-N—((R)-2,2,2-trifluoro-1-(3-isopropylphenyl)ethyl)propane-2-sulfinamide

Tetra-n-butylammonium difluorotriphenylsilicate (TBAT) (1.19 g, 2.13mmol) and (trifluoromethyl)trimethylsilane (TMS-CF₃) (0.371 mL, 2.33mmmol) was added to a solution of(S,E)-N-(3-isopropylbenzylidene)-2-methylpropane-2-sulfinamide (0.487 g,1.937 mmol) in anhydrous THF (16 mL) at −20° C. under argon. Thereaction was allowed to proceed for ˜2 h where the starting materialappeared to have been consumed as determined by analytical-HPLC. Asaturated solution of NH₄Cl (20 mL) was added to quench and the mixturewas extracted with EtOAc (100 mL×3) and dried over Na₂SO₄. The organicpartition was then concentrated to an oil and the title compound wasisolated by flash chromatography using silica gel (EtOAc:Hexanes).ESI-MS (m/z): 321 [M+1]⁺.

Step 3: (R)-2,2,2-trifluoro-1-(3-isopropylphenyl)ethanaminium Chloride

The title compound was prepared following the same general syntheticprocedure as described in Step 2, Example 2, using(S)-2-methyl-N—((R)-2,2,2-trifluoro-1-(3-isopropylphenyl)ethyl)propane-2-sulfinamideinstead of 4-(tert-butyl)benzaldehyde.

Step 4:(R)-4′-((2,3-dimethyl-((2,2,2-trifluoro-1-(3-isopropylphenyl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 8-9, Example 1, using(R)-2,2,2-trifluoro-1-(3-isopropylphenyl)ethanamine and1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. ESI-MS (m/z): 599 [M+H]⁺.

Example 140:(S)-4′-((5-((cyclopropyl(3-isopropylphenyl)methyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

Step 1: (S)-cyclopropyl(3-isopropylphenyl)methanaminium Chloride

The title compound was prepared following the same general syntheticprocedure as described in Steps 1-2, Example 2, using3-isopropylbenzaldehyde and cyclopropylmagnesium bromide instead of4-(tert-butyl)benzaldehyde and methylmagnesium bromide.

Step 2: Example:(S)-4′((5-((cyclopropyl(3-isopropylphenyl)methyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 1-2, Example 19, using(S)-cyclopropyl(3-isopropylphenyl)methanamine and1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. ESI-MS (m/z): 571 [M+H]⁺.

Example 141:(R)-4′-((5-((1-(2,6-dichlorophenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

Step 1: (R)-1-(2,6-dichlorophenyl)ethanamine

The title compound was prepared following the same general protocol asdescribed in Step 1-2, Example 2, using 2,6-dichlorobenzaldehyde.

Step 2:(R)-4′-((5-((1-(2,6-dichlorophenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 8-9, Example 1, using(R)-1-(2,6-dichlorophenyl)ethanamine and1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. ESI-MS (m/z): 571 [M+H]⁺.

Example 142:(S)-4′-((5-((1-(2,6-dichlorophenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

Step 1: (S)-1-(2,6-dichlorophenyl)ethanamine

The title compound was prepared following the same general protocol asdescribed in Step 1-2, Example 2, using 2,6-dichlorobenzaldehyde.

Step 2:(S)-4′-((5-((1-(2,6-dichlorophenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 8-9, Example 1, using(S)-1-(2,6-dichlorophenyl)ethanamine and1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. ESI-MS (m/z): 571 [M+H]⁺.

Example 143:(S)-4′-((5-((1-(benzo[d][1,3]dioxol-4-yl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

Step 1: (S)-1-(benzo[d][1,3]dioxol-4-yl)ethanamine

The title compound was prepared following the same general protocol asdescribed in Step 1-2, Example 2, usingbenzo[d][1,3]dioxole-4-carbaldehyde.

Step 2:(S)-4′-((5-((1-(benzo[d][1,3]dioxol-4-yl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 8-9, Example 1, using(S)-1-(benzo[d][1,3]dioxol-4-yl)ethanamine and1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. ESI-MS (m/z): 547 [M+H]⁺.

Example 144:(S)-4′-((2,3-dimethyl-5-((1-(pyridin-2-yl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

Step 1: (S)-1-(pyridin-2-yl)ethanamine

The title compound was prepared following the same general protocol asdescribed in Step 1-2, Example 2, using the picolinaldehyde.

Step 2:(S)-4′-((2,3-dimethyl-5-((1-(pyridin-2-yl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 8-9, Example 1, using the(S)-1-(pyridin-2-yl)ethanamine and the1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. ESI-MS (m/z): 504 [M+H]⁺.

Example 145:(S)-4′-((5-((1-(3-fluoro-2-methylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

Step 1: (S)-1-(3-fluoro-2-methylphenyl)ethanaminium Chloride

The title compound was prepared following the same general syntheticprocedure as described in Steps 1-2, Example 2, using3-fluoro-2-methylbenzaldehyde instead of 4-(tert-butyl)benzaldehyde.

Step 2:(S)-4′-((5-((1-(3-fluoro-2-methylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 8-9, Example 1, using the(S)-1-(3-fluoro-2-methylphenyl)ethanamine and the1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. ESI-MS (m/z): 535 [M+H]⁺.

Example 146:(S)-4′-((5-((1-(3-fluoro-5-methoxyphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

Step 1: (S)-1-(3-fluoro-5-methoxyphenyl)ethanaminium Chloride

The title compound was prepared following the same general syntheticprocedure as described in Steps 1-2, Example 2, using3-fluoro-5-methoxybenzaldehyde instead of 4-(tert-butyl)benzaldehyde.

Step 2:(S)-4′-((5-((1-(3-fluoro-5-methoxyphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 8-9, Example 1, using the(S)-1-(3-fluoro-5-methoxyphenyl)ethanamine and the1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. ESI-MS (m/z): 551 [M+H]⁺.

Example 147:(S)-4′-((5-((1-(3,5-dimethoxyphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

Step 1: (S)-1-(3,5-dimethoxyphenyl)ethanaminium Chloride

The title compound was prepared following the same general syntheticprocedure as described in Steps 1-2, Example 2, using3,5-dimethoxybenzaldehyde instead of 4-(tert-butyl)benzaldehyde.

Step 2:(S)-4′-((5-((1-(3,5-dimethoxyphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 8-9, Example 1, using the(S)-1-(3,5-dimethoxyphenyl)ethanamine and the1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. ESI-MS (m/z): 563 [M+H]⁺.

Example 148:(S)-4′-((5-((1-(3-chloropyridin-4-yl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

Step 1: (S)-1-(3-chloropyridin-4-yl)ethanamine

The title compound was prepared following the same general protocol asdescribed in Step 1-2, Example 2, using the 3-chloroisonicotinaldehyde.

Step 2:(S)-4′-((5-((1-(3-chloropyridin-4-yl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 8-9, Example 1, using the(S)-1-(3-chloropyridin-4-yl)ethanamine and the1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. ESI-MS (m/z): 538/539/540 [M+H]⁺.

Example 149:(S)-4′-((2,3-dimethyl-5-((1-(quinolin-4-yl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

Step 1: (S)-1-(quinolin-4-yl)ethanamine

The title compound was prepared following the same general protocol asdescribed in Step 1-2, Example 2, using the quinoline-4-carbaldehyde.

Step 2:(S)-4′-((2,3-dimethyl-5-((1-(quinolin-4-yl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 8-9, Example 1, using the(S)-1-(quinolin-4-yl)ethanamine and the1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. ESI-MS (m/z): 554 [M+H]⁺.

Example 150:(S)-4′-((5-((1-(2,4-difluorophenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

Step 1: (S)-1-(2,4-difluorophenyl)ethanaminium Chloride

The title compound was prepared following the same general syntheticprocedure as described in Steps 1-2, Example 2, using2,4-difluorobenzaldehyde instead of 4-(tert-butyl)benzaldehyde.

Step 2:(S)-4′-((5-((1-(2,4-difluorophenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 8-9, Example 1, using the(S)-1-(2,4-difluorophenyl)ethanamine and the1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. ESI-MS (m/z): 539 [M+H]⁺.

Example 151:(S)-4′-((5-((1-(3-ethoxyphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

Step 1: (S)-(3-ethoxyphenyl)ethanamine

The title compound was prepared following the same general protocol asdescribed in Step 1-2, Example 2, using the 3-ethoxybenzaldehyde.

Step 2:(S)-4′-((5-((1-(3-ethoxyphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 8-9, Example 1, using the(S)-1-(3-ethoxyphenyl)ethanamine and the1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. ESI-MS (m/z): 545 [M+H]⁺.

Example 152:(S)-4′-((2,3-dimethyl-5-((1-(naphthalen-1-yl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

Step 1: (S)-1-(naphthalen-1-yl)ethanamine

The title compound was prepared following the same general protocol asdescribed in Step 1-2, Example 2, using the 1-naphthaldehyde.

Step 2:(S)-4′-((2,3-dimethyl-5-((1-(naphthalen-1-yl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 8-9, Example 1, using the(S)-1-(naphthalen-1-yl)ethanamine and the1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. ESI-MS (m/z): 553 [M+H]⁺.

Example 153:(S)-4′-((2,3-dimethyl-5-((1-(4-(trifluoromethoxy)phenyl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

Step 1: (S)-1-(4-(trifluoromethoxy)phenyl)ethanaminium chloride

The title compound was prepared following the same general syntheticprocedure as described in Steps 1-2, Example 2, using4-(trifluoromethoxy)benzaldehyde instead of 4-(tert-butyl)benzaldehyde.

Step 2:(S)-4′-((2,3-dimethyl-5-((1-(4-(trifluoromethoxy)phenyl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 8-9, Example 1, using the(S)-1-(4-(trifluoromethoxy)phenyl)ethanamine and the1-((T-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. ESI-MS (m/z): 587 [M+H]⁺.

Example 154:(S)-4′-((2,3-dimethyl-5-((1-(4-(trifluoromethyl)phenyl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

Step 1: (S)-1-(4-(trifluoromethyl)phenyl)ethanamine

The title compound was prepared following the same general protocol asdescribed in Step 1-2, Example 2, using the4-trifluoromethylbenzaldehyde.

Step 2:(S)-4′-((2,3-dimethyl-5-((1-(4-(trifluoromethyl)phenyl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 8-9, Example 1, using the(S)-1-(4-(trifluoromethyl)phenyl)ethanamine and the1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. ESI-MS (m/z): 571 [M+H]⁺.

Example 155:(S)-4′-((5-((1-(3-isopropylphenyl)-3-methylbutyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

Step 1: (S)-1-(3-isopropylphenyl)-3-methylbutan-1-amine

The title compound was prepared following the same general syntheticprocedure as described in Steps 1-2, Example 2, using3-isopropylbenzaldehyde and isobutylmagnesium chloride instead of4-(tert-butyl)benzaldehyde and methylmagnesium bromide.

Step 2:(S)-4′-((5-((1-(3-isopropylphenyl)-3-methylbutyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 8-9, Example 1, using the(S)-1-(3-isopropylphenyl)-3-methylbutan-1-amine and the1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. ESI-MS (m/z): 587 [M+H]⁺.

Example 156:(R)-4′-((5-((1-(3-isopropylphenyl)-2-methylpropyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

Step 1: (R)-1-(3-isopropylphenyl)-2-methylpropan-1-aminium chloride

The title compound was prepared following the same general syntheticprocedure as described in Steps 1-2, Example 2, using3-isopropylbenzaldehyde and 2-propyl-magnesium chloride instead of4-(tert-butyl)benzaldehyde and methylmagnesium bromide.

Step 2:(R)-4′-((5-((1-(3-isopropylphenyl)-2-methylpropyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 8-9, Example 1, using the(R)-1-(3-isopropylphenyl)-2-methylpropan-1-amine and the1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. ESI-MS (m/z): 573 [M+H]⁺.

Example 157:(S)-4′-((5-((1-(3-isopropylphenyl)-2-methylpropyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

Step 1: (R)-1-(3-isopropylphenyl)-2-methylpropan-1-aminium chloride

The title compound was prepared following the same general syntheticprocedure as described in Steps 1-2, Example 2, using3-isopropylbenzaldehyde and 2-propyl-magnesium chloride instead of4-(tert-butyl)benzaldehyde and methylmagnesium bromide.

Step 2:(S)-4′-((5-((1-(3-isopropylphenyl)-2-methylpropyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 8-9, Example 1, using the(S)-1-(3-isopropylphenyl)-2-methylpropan-1-amine and the1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. ESI-MS (m/z): 573 [M+H]⁺.

Example 158:(S)-4′-((5-((1-(3-fluorophenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

Step 1: (S)-1-(3-fluorophenyl)ethanamine

The title compound was prepared following the same general protocol asdescribed in Step 1-2, Example 2, using the 3-fluorobenzaldehyde.

Step 2:(S)-4′-((5-((1-(3-fluorophenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 8-9, Example 1, using the(S)-1-(3-fluorophenyl)ethanamine and the1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. ESI-MS (m/z): 521 [M+H]⁺.

Example 159:(S)-4′-((5-((1-(2-chlorophenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

Step 1: (S)-1-(2-chlorophenyl)ethanamine

The title compound was prepared following the same general protocol asdescribed in Step 1-2, Example 2, using the 2-chlorobenzaldehyde.

Step 2:(S)-4′-((5-((1-(2-chlorophenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 8-9, Example 1, using the(S)-1-(2-chlorophenyl)ethanamine and the1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. ESI-MS (m/z): 537/538/539 [M+H]⁺.

Example 160:(S)-4′-((5-((1-(2-fluorophenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

Step 1: (S)-1-(2-fluorophenyl)ethanamine

The title compound was prepared following the same general protocol asdescribed in Step 1-2, Example 2, using the 2-fluorobenzaldehyde.

Step 2:(S)-4′-((5-((1-(2-fluorophenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 8-9, Example 1, using the(S)-1-(2-fluorophenyl)ethanamine and the1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. ESI-MS (m/z): 521 [M+H]⁺.

Example 161:(R)-4′-((5-((1-(3-methoxyphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 8-9, Example 1, using the(R)-1-(3-methoxyphenyl)ethanamine and the1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. ESI-MS (m/z): 533 [M+H]⁺.

Example 162:(R)-4′-((5-((1-(3-chlorophenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 8-9, Example 1, using the(R)-1-(3-chlorophenyl)ethanamine and the1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. ESI-MS (m/z): 537/538/539 [M+H]⁺.

Example 163:(S)-4′-((5-((1-(4-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 1-2-3, Example 137, using the (S)-tert-butyl4′-((5-((1-(4-bromophenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylate.ESI-MS (m/z): 545 [M+H]⁺.

Example 164:4′-((5-((2,4-difluorobenzyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 8-9, Example 1, using the(2,4-difluorophenyl)methanamine and the1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. ESI-MS (m/z): 525 [M+H]⁺.

Example 165:4′-((5-((4-chloro-2-(trifluoromethyl)benzyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 8-9, Example 1, using the(4-chloro-2-(trifluoromethyl)phenyl)methanamine and the1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. ESI-MS (m/z): 591 [M+H]⁺.

Example 166:(R)-4′-((5-((1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 1-2-3, Example 137, using the (R)-tert-butyl4′-((5-((1-(3-bromophenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylate.ESI-MS (m/z): 545 [M+H]⁺.

Example 167:4′-((5-((2-fluoro-4-(trifluoromethyl)benzyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 8-9, Example 1, using the(2-fluoro-4-(trifluoromethyl)phenyl)methanamine and the1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. ESI-MS (m/z): 575 [M+H]⁺.

Example 168:4′-((5-((2,4-dichlorobenzyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 8-9, Example 1, using the(2,4-dichlorophenyl)methanamine and the1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. ESI-MS (m/z): 557/559 [M+H]⁺.

Example 169:(R)-4′-((2,3-dimethyl-5-((1-(pyridin-4-yl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

Step 1: (R)-1-(pyridin-4-yl)ethanamine

The title compound was prepared following the same general protocol asdescribed in Step 1-2, Example 2, using the isonicotinaldehyde.

Step 2:(R)-4′-((2,3-dimethyl-5-((1-(pyridin-4-yl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 8-9, Example 1, using the(R)-1-(pyridin-4-yl)ethanamine and the1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. ESI-MS (m/z): 504 [M+H]⁺.

Example 170:(S)-4′-((5-((1-(2-chloro-3-fluorophenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

Step 1: (S)-1-(2-chloro-3-fluorophenyl)ethanamine

The title compound was prepared following the same general protocol asdescribed in Step 1-2, Example 2, using the2-chloro-3-fluorobenzaldehyde.

Step 2:(S)-4′-((5-((1-(2-chloro-3-fluorophenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 8-9, Example 1, using the(S)-1-(2-chloro-3-fluorophenyl)ethanamine and the1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. ESI-MS (m/z): 504 [M+H]⁺.

Example 171:(R)-4′-((5-((1-(2,3-dichlorophenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

Step 1: (R)-1-(2,3-dichlorophenyl)ethanamine

The title compound was prepared following the same general protocol asdescribed in Step 1-2, Example 2, using the 2,3-dichlorobenzaldehyde.

Step 2:(R)-4′-((5-((1-(2,3-dichlorophenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 8-9, Example 1, using the(R)-1-(2,3-dichlorophenyl)ethanamine and the1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. ESI-MS (m/z): 571 [M+H]⁺.

Example 172:(S)-4′-((5-((1-(2,5-bis(trifluoromethyl)phenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

Step 1: (S)-1-(2,5-bis(trifluoromethyl)phenyl)ethanamine

The title compound was prepared following the same general protocol asdescribed in Step 1-2, Example 2, using the2,5-bis(trifluoromethyl)benzaldehyde.

Step 2:(S)-4′-((5-((1-(2,5-bis(trifluoromethyl)phenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 8-9, Example 1, using the(S)-1-(2,5-bis(trifluoromethyl)phenyl)ethanamine and the1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. ESI-MS (m/z): 639 [M+H]⁺.

Example 173:(R)-4′-((5-((1-(2,5-bis(trifluoromethyl)phenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

Step 1: (R)-1-(2,5-bis(trifluoromethyl)phenyl)ethanamine

The title compound was prepared following the same general protocol asdescribed in Step 1-2, Example 2, using the2,5-bis(trifluoromethyl)benzaldehyde.

Step 2:(R)-4′-((5-((1-(2,5-bis(trifluoromethyl)phenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 8-9, Example 1, using the(R)-1-(2,5-bis(trifluoromethyl)phenyl)ethanamine and the1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. ESI-MS (m/z): 639 [M+H]⁺.

Example 174:(S)-4′-((5-((1-(3-chlorophenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 8-9, Example 1, using the(S)-1-(3-chlorophenyl)ethanamine and the1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. ESI-MS (m/z): 537/538/539 [M+H]⁺.

Example 175:(S)-4′-((5-((1-(2-methoxyphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 8-9, Example 1, using the(S)-1-(2-methoxyphenyl)ethanamine and the1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. ESI-MS (m/z): 533 [M+H]⁺.

Example 176:(S)-4′-((2,3-dimethyl-5-((1-(3-(trifluoromethyl)phenyl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

Step 1: (S)-1-(3-(trifluoromethyl)phenyl)ethanaminium Chloride

The title compound was prepared following the same general syntheticprocedure as described in Steps 1-2, Example 2, using3-(trifluoromethyl)benzaldehyde instead of 4-(tert-butyl)benzaldehyde.

Step 2:(S)-4′-((2,3-dimethyl-5-((1-(3-(trifluoromethyl)phenyl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 8-9, Example 1, using the(S)-1-(3-(trifluoromethyl)phenyl)ethanamine and the1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. ESI-MS (m/z): 571 [M+H]⁺.

Example 177:(S)-4′-((5-((1-(3-fluoro-2-methoxyphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

Step 1: (S)-1-(3-fluoro-2-methoxyphenyl)ethanamine

The title compound was prepared following the same general protocol asdescribed in Step 1-2, Example 2, using the3-fluoro-2-methoxybenzaldehyde.

Step 2:(S)-4′-((5-((1-(3-fluoro-2-methoxyphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 1-2, Example 2, using the(S)-1-(3-fluoro-2-methoxyphenyl)ethanamine and the1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. ESI-MS (m/z): 551 [M+H]⁺.

Example 178:(S)-4′-((5-((1-(3-isopropylphenyl)pentyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

Step 1: (S)-1-(3-isopropylphenyl)pentan-1-aminium Chloride

The title compound was prepared following the same general syntheticprocedure as described in Steps 1-2, Example 2, using3-isopropylbenzaldehyde and n-butyl-magnesium bromide instead of4-(tert-butyl)benzaldehyde and methylmagnesium bromide.

Step 2:(S)-4′-((5-((1-(3-isopropylphenyl)pentyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 8-9, Example 1, using the(S)-1-(3-isopropylphenyl)pentan-1-amine and the1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. ESI-MS (m/z): 587 [M+H]⁺.

Example 179:(S)-4′-((2,3-dimethyl-5-((1-(p-tolyl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 8-9, Example 1, using the (S)-1-(p-tolyl)ethanamineand the1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. ESI-MS (m/z): 517 [M+H]⁺.

Example 180:4′-((5-((2-(4-bromophenyl)propan-2-yl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 8-9, Example 1, using the2-(4-bromophenyl)propan-2-amine and the1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. ESI-MS (m/z): 595/597 [M+H]⁺.

Example 181:(R)-4′-((2,3-dimethyl-5-((1-(quinolin-4-yl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

Step 1: (R)-1-(quinolin-4-yl)ethanamine

The title compound was prepared following the same general protocol asdescribed in Step 1-2, Example 2, using the quinoline-4-carbaldehyde.

Step 2:(R)-4′-((2,3-dimethyl-5-((1-(quinolin-4-yl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 8-9, Example 1, using the(R)-1-(quinolin-4-yl)ethanamine and the1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. ESI-MS (m/z): 554 [M+H]⁺.

Example 182:4′-((5-((3-isopropylbenzyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 8-9, Example 1, using the(3-isopropylphenyl)methanamine and the1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. ESI-MS (m/z): 531 [M+H]⁺.

Example 183:(S)-4′-((5-((1-(3-isopropylphenyl)-2-phenylethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

Step 1: (S)-1-(3-isopropylphenyl)-2-phenylethanaminium chloride

The title compound was prepared following the same general syntheticprocedure as described in Steps 1-2, Example 2, using3-isopropylbenzaldehyde and benzylmagnesium bromide instead of4-(tert-butyl)benzaldehyde and methylmagnesium bromide.

Step 2:(S)-4′-((5-((1-(3-isopropylphenyl)-2-phenylethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 8-9, Example 1, using the(S)-1-(3-isopropylphenyl)-2-phenylethanamine and the1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. ESI-MS (m/z): 587 [M+H]⁺.

Example 184:(S)—N-(1-(4-(tert-butyl)phenyl)ethyl)-1-((2′-cyano-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxamide

The title compound was prepared following the same general protocol asdescribed in Step 5, Example 34, using the(S)-1-(4-(tert-butyl)phenyl)ethanamine instead of the1-phenylpropan-1-amine. ESI-MS (m/z): 540 [M+H]⁺.

Example 185:(S)—N-(1-(3-(tert-butyl)phenyl)ethyl)-1-((2′-cyano-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxamide

The title compound was prepared following the same general protocol asdescribed in Step 5, Example 34, using the(S)-1-(3-(tert-butyl)phenyl)ethanamine instead of the1-phenylpropan-1-amine. ESI-MS (m/z): 540 [M+H]⁺.

Example 186:(S)-1-((2′-cyano-[1,1′-biphenyl]-4-yl)methyl)-N-(1-(4-isopropylphenyl)ethyl)-2,3-dimethyl-1H-indole-5-carboxamide

The title compound was prepared following the same general protocol asdescribed in Step 1-2-3, Example 137, using the(S)—N-(1-(4-bromophenyl)ethyl)-1-((2′-cyano-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxamide.ESI-MS (m/z): 526 [M+H]⁺.

Example 187:(R)-1-((2′-(1H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-N-(1-(3-bromophenyl)ethyl)-2,3-dimethyl-1H-indole-5-carboxamide

Step 1:(R)—N-(1-(3-bromophenyl)ethyl)-1-((2′-cyano-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxamide

The title compound was prepared following the same general protocol asdescribed in Step 5, Example 34, using the(R)-1-(3-bromophenyl)ethanamine instead of the 1-phenylpropan-1-amine.

Step 2:(R)-1-((2′-(1H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-N-(1-(3-bromophenyl)ethyl)-2,3-dimethyl-1H-indole-5-carboxamide

The title compound was prepared following the same general protocol asdescribed in Example 36, using the(R)—N-(1-(3-bromophenyl)ethyl)-1-((2′-cyano-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxamide.ESI-MS (m/z): 605/607 [M+H]⁺.

Example 188:(S)-1-((2′-(1H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-N-(1-(3-cyclopropylphenyl)ethyl)-2,3-dimethyl-1H-indole-5-carboxamide

Step 1:(S)-1-((2′-cyano-[1,1′-biphenyl]-4-yl)methyl)-N-(1-(3-cyclopropylphenyl)ethyl)-2,3-dimethyl-1H-indole-5-carboxamide

The title compound was prepared following the same general protocol asdescribed in Step 5, Example 34, using the(S)-1-(3-cyclopropylphenyl)ethanamine instead of the1-phenylpropan-1-amine. ESI-MS (m/z): 524 [M+H]⁺.

Step 2:(S)-1-((2′-(1H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-N-(1-(3-cyclopropylphenyl)ethyl)-2,3-dimethyl-1H-indole-5-carboxamide

The title compound was prepared following the same general protocol asdescribed in Example 36, using the(S)-1-((2′-cyano-[1,1′-biphenyl]-4-yl)methyl)-N-(1-(3-cyclopropylphenyl)ethyl)-2,3-dimethyl-1H-indole-5-carboxamide.ESI-MS (m/z): 567 [M+H]⁺.

Example 189:(S)-2′-((5-((1-phenylpropyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-4-carboxylicAcid

The title compound was prepared following the same protocol as describedin Step 3-4, Example 120 using the (S)-1-phenylpropylamine instead ofthe (S)-1-(4-bromophenyl)ethanamine. ESI-MS (m/z): 489 [M+H]⁺.

Example 190:(R)-2′-((5-((1-phenylpropyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-4-carboxylicAcid

The title compound was prepared following the same protocol as describedin Step 3-4, Example 120 using the (R)-1-phenylpropylamine instead ofthe (S)-1-(4-bromophenyl)ethanamine. ESI-MS (m/z): 489 [M+H]⁺.

Example 191:(S)-T-((5-((1-phenylpropyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-3-carboxylicAcid

The title compound was prepared following the same protocol as describedin Step 3-4, Example 122 using the (S)-1-phenylpropylamine instead ofthe (S)-1-(4-bromophenyl)ethanamine. ESI-MS (m/z): 489 [M+H]⁺.

Example 192:(R)-2′-((5-((1-phenylpropyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-3-carboxylicAcid

The title compound was prepared following the same protocol as describedin Step 2-3, Example 122 using the (R)-1-phenylpropylamine instead ofthe (S)-1-(4-bromophenyl)ethanamine. ESI-MS (m/z): 489 [M+H]⁺.

Example 193:(R)-2′-((2,3-dimethyl-5-((1-phenylpropyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-3-carboxylicAcid

The title compound was prepared following the same protocol as describedin Step 4-5, Example 124 using the (R)-1-phenylpropylamine instead ofthe (S)-1-(4-bromophenyl)ethanamine. ESI-MS (m/z): 489 [M+H]⁺.

Example 194:(S)-2′-((2,3-dimethyl-5-((1-phenylpropyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-3-carboxylicAcid

The title compound was prepared following the same protocol as describedin Step 4-5, Example 124 using the (S)-1-phenylpropylamine instead ofthe (S)-1-(4-bromophenyl)ethanamine. ESI-MS (m/z): 489 [M+H]⁺.

Example 195:(R)-2′-((2,3-dimethyl-5-((1-phenylpropyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-4-carboxylicAcid

The title compound was prepared following the same protocol as describedin Step 2-3, Example 127 using the (R)-1-phenylpropylamine instead ofthe (S)-1-(4-bromophenyl)ethanamine. ESI-MS (m/z): 489 [M+H]⁺.

Example 196:(S)-2′-((2,3-dimethyl-5-((1-phenylpropyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-4-carboxylicAcid

The title compound was prepared following the same protocol as describedin Step 2-3, Example 127 using the (S)-1-phenylpropylamine instead ofthe (S)-1-(4-bromophenyl)ethanamine. ESI-MS (m/z): 489 [M+H]⁺.

Example 197:(S)-4′-((5-((1-(3-chloro-4-methoxyphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

Step 1: (S)-1-(3-chloro-4-methoxyphenyl)ethanaminium Chloride

The title compound was prepared following the same general syntheticprocedure as described in Steps 1-2, Example 2, using3-chloro-4-methoxybenzaldehyde instead of 4-(tert-butyl)benzaldehyde.

Step 2:(S)-4′-((5-((1-(3-chloro-4-methoxyphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general syntheticprocedure as described in Steps 3-4, Example 2, starting with(S)-1-(3-chloro-4-methoxyphenyl)ethanaminium chloride and1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid instead of (S)-1-(4-(tert-butyl)phenyl)ethanaminium chloride and1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. ESI-MS (m/z): 567 [M+1]⁺.

Example 198:(S)-4′-((5-((1-(3-isopropylphenyl)propyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

Step 1: (S)-1-(3-isopropylphenyl)propan-1-aminium Chloride

The title compound was prepared following the same general syntheticprocedure as described in Steps 1-2, Example 2, using3-isopropylbenzaldehyde and ethylmagnesium bromide instead of4-(tert-butyl)benzaldehyde and methylmagnesium bromide.

Step 2:(S)-4′-((5-((1-(3-isopropylphenyl)propyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general syntheticprocedure as described in Steps 3-4, Example 2, starting with(S)-1-(3-isopropylphenyl)propan-1-aminium chloride and1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid instead of (S)-1-(4-(tert-butyl)phenyl)ethanaminium chloride and1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. ESI-MS (m/z): 558 [M+1]⁺.

Example 199:(S)-4′-((5-((1-(3-isopropoxyphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

Step 1: (S)-1-(3-isopropoxyphenyl)ethanaminium Chloride

The title compound was prepared following the same general syntheticprocedure as described in Steps 1-2, Example 2, using3-isopropoxybenzaldehyde instead of 4-(tert-butyl)benzaldehyde.

Step 2:(S)-4′-((5-((1-(3-isopropoxyphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general syntheticprocedure as described in Steps 3-4, Example 2, starting with(S)-1-(3-isopropoxyphenyl)ethanaminium chloride and1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid instead of (S)-1-(4-(tert-butyl)phenyl)ethanaminium chloride and1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. ESI-MS (m/z): 560 [M+1]⁺.

Example 200:(S)-4′-((5-((1-(4-(tert-butoxy)phenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

Step 1: (S)-1-(4-(tert-butoxy)phenyl)ethanaminium Chloride

The title compound was prepared following the same general syntheticprocedure as described in Steps 1-2, Example 2, using4-(tert-butoxy)benzaldehyde instead of 4-(tert-butyl)benzaldehyde.

Step 2:(S)-4′-((5-((1-(4-(tert-butoxy)phenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general syntheticprocedure as described in Steps 3-4, Example 2, starting with(S)-1-(4-(tert-butoxy)phenyl)ethanaminium chloride and1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid instead of (S)-1-(4-(tert-butyl)phenyl)ethanaminium chloride and1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. ESI-MS (m/z): 574 [M+1]⁺.

Example 201:(S)-4′-((5-((1-(4-isopropoxyphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

Step 1: (S)-1-(4-isopropoxyphenyl)ethanaminium Chloride

The title compound was prepared following the same general syntheticprocedure as described in Steps 1-2, Example 2, using4-isopropoxybenzaldehyde instead of 4-(tert-butyl)benzaldehyde.

Step 2:(S)-4′-((5-((1-(4-isopropoxyphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general syntheticprocedure as described in Steps 3-4, Example 2, starting with(S)-1-(4-isopropoxyphenyl)ethanaminium chloride and1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid instead of (S)-1-(4-(tert-butyl)phenyl)ethanaminium chloride and1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. ESI-MS (m/z): 560 [M+1]⁺.

Example 202:(S)-4′-((5-((1-(1-((benzyloxy)carbonyl)piperidin-4-yl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

Step 1: (S)-1-(1-((benzyloxy)carbonyl)piperidin-4-yl)ethanaminiumChloride

The title compound was prepared following the same general syntheticprocedure as described in Steps 1-2, Example 2, using benzyl4-formylpiperidine-1-carboxylate instead of 4-(tert-butyl)benzaldehyde.ESI-MS (m/z): 263 [M+1]⁺.

Step 2:(S)-4′-((5-((1-(1-((benzyloxy)carbonyl)piperidin-4-yl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general syntheticprocedure as described in Steps 3-4, Example 2, starting with((S)-1-(1-((benzyloxy)carbonyl)piperidin-4-yl)ethanaminium chloride and1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid instead of (S)-1-(4-(tert-butyl)phenyl)ethanaminium chloride and1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. ESI-MS (m/z): 643 [M+1]⁺.

Example 203:(S)-4′-((5-((1-(1-(benzylcarbamoyl)piperidin-4-yl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid 2753

The title compound was prepared from(S)-4′-((5-((1-(1-((benzyloxy)carbonyl)piperidin-4-yl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylic-acid(0.175 g, 0.250 mmol) following palladium catalyzed hydrogenation (18mg, 10% Pd/c) in AcOH (5 mL) and subsequent coupling of the resultingpiperidine((S)-tert-butyl-4′-((2,3-dimethyl-5-((1-(piperidin-4-yl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylate)with benzyl isocyanate (6.8 mg, 0.049 mmol) in dicholoromethane (DCM) (1mL)/di-isopropylethylamine (9.2 μL, 0.053 mmol) and then removal oft-butyl ester in TFA/DCM (1:1, 2 mL). Completion at each synthetic stepwas monitored by analytical HPLC and the title compound was isolated byreverse phase prep-HPLC (MeOH/Acetonitrile/water) ESI-MS (m/z): 642[M+1]⁺.

Example 204:(S)-4′-((5-((1-((benzyloxy)carbonyl)pyrrolidin-3-yl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general syntheticprocedure as described in Steps 3-4, Example 2, starting with (S)-benzyl3-aminopyrrolidine-1-carboxylate and1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid instead of (S)-1-(4-(tert-butyl)phenyl)ethanaminium chloride and1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. ESI-MS (m/z): 601 [M+1]⁺.

Example 205:(R)-4′-((5-((1-(5-fluoro-2-methoxyphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Steps 1-4, Example 1, using 5-fluoro-2-methoxybenzaldehydeand1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. LC-MS 551.2 (M+H).

Example 206:(S)-4′-((5-((1-(5-fluoro-2-methoxyphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Steps 1-4, Example 1, using 5-fluoro-2-methoxybenzaldehydeand1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. LC-MS 551.2 (M+H).

Example 207:(R)-4′-((2,3-dimethyl-5-((1-(2-(trifluoromethyl)phenyl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Steps 1-4, Example 1, using 2-trifluoromethylbenzaldehydeand1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. LC-MS 571.2 (M+H).

Example 208:(S)-4′-((2,3-dimethyl-5-((1-(2-(trifluoromethyl)phenyl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Steps 1-4, Example 1, using 2-trifluoromethylbenzaldehydeand1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. LC-MS 571.6 (M+H).

Example 209:(R)-4′-((5-((1-(2,4-bis(trifluoromethyl)phenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Steps 1-4, Example 1, using2,4-bistrifluoromethylbenzaldehyde and1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. LC-MS 639.2 (M+H).

Example 210:(S)-4′-((5-((1-(2,4-bis(trifluoromethyl)phenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Steps 1-4, Example 1, using2,4-bistrifluoromethylbenzaldehyde and1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. LC-MS 639.2 (M+-H).

Example 211:(S)-4′-((5-((1-(2-fluoro-5-methylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Steps 1-4, Example 1, using 2-fluoro-5-methylbenzaldehydeand1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. LC-MS 535.2 (M+H).

Example 212:(S)-4′-((5-((1-cyclohexylethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Steps 1-4, Example 1, using cyclohexanecarboxaldehyde and1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. LC-MS 509.2 (M+H).

Example 213:4′-((5-(((1R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-2-yl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Steps 1-4, Example 1, using2,3-dihydrobenzo[b][1,4]dioxine-2-carbaldehyde and1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. LC-MS 561.2 (M+H).

Example 214:4′-((5-(((1S)-1-(2,3-dihydrobenzo[b][1,4]dioxin-2-yl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Steps 1-4, Example 1, using2,3-dihydrobenzo[b][1,4]dioxine-2-carbaldehyde and1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. LC-MS 561.2 (M+H).

Example 215:(R)-4′-((5-((1-(3,5-difluoropyridin-4-yl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Steps 1-4, Example 1, using 3,5-difluoroisonicotinaldehydeand1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. LC-MS 540.2 (M+H).

Example 216:(S)-4′-((5-((1-(3,5-difluoropyridin-4-yl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Steps 1-4, Example 1, using 3,5-difluoroisonicotinaldehydeand1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. LC-MS 540.2 (M+H).

Example 217:(S)-4′-((2,3-dimethyl-5-((1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Steps 1-4, Example 1, using6-(trifluoromethyl)nicotinaldehyde and1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. LC-MS 572.2 (M+H).

Example 218:(S)-4′-((5-((1-(2,3-dihydrobenzofuran-5-yl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Steps 1-4, Example 1, using2,3-dihydrobenzofuran-5-carbaldehyde and1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. LC-MS 545.2 (M+H).

Example 219:(S)-4′-((5-((1-(3,5-dichlorophenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Steps 1-4, Example 1, using 2,4-dichlorobenzaldehyde and1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. LC-MS 571.1 (M+H).

Example 220:(S)-4′-((5-((1-(3,4-dichlorophenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Steps 1-4, Example 1, using 3,4-dichlorobenzaldehyde and1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. LC-MS 571.1 (M+).

Example 221:(S)-4′-((5-((1-(2-fluoro-5-(trifluoromethyl)phenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Steps 1-4, Example 1, using2-fluoro-5-trifluoromethylbenzaldehyde and1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. LC-MS 589.1 (M+H).

Example 222:(S)-4′-((5-((1-(4-chloro-3-(trifluoromethyl)phenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Steps 1-4, Example 1, using3-trifluoromethyl-4-chlorobenzaldehyde and1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. LC-MS 606.1 (M+H).

Example 223:(S)-4′-((5-((1-(2-methoxy-4-(trifluoromethyl)phenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Steps 1-4, Example 1, using2-methoxy-4-trifluoromethylbenzaldehyde and1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. LC-MS 601.2 (M+H).

Example 224:(R)-4′-((5-((1-(2-methoxy-4-(trifluoromethyl)phenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Steps 1-4, Example 1, using2-methoxy-4-trifluoromethylbenzaldehyde and1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. LC-MS 601.2 (M+H).

Example 225:(S)-4′-((5-((1-(4-ethylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Steps 1-4, Example 1, using 4-ethylbenzaldehyde and1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. LC-MS 531.2 (M+H).

Example 226:(S)-4′-((5-((1-(4-chloro-2-methylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 8-9, Example 1, using the(S)-1-(4-chloro-2-methylphenyl)ethanamine hydrochloride and the1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. ESI-MS (m/z): 551 [M+H]⁺.

Example 227:(S)-4′-((5-((1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 8-9, Example 1, using the(S)-1-(4-fluoro-2-(trifluoromethyl)phenyl)ethanamine hydrochloride andthe1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. ESI-MS (m/z): 589 [M+H]⁺.

Example 228:(S)-4′-((5-((1-(3-fluoro-4-(trifluoromethyl)phenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 8-9, Example 1, using the(S)-1-(3-fluoro-4-(trifluoromethyl)phenyl)ethanamine hydrochloride andthe1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. ESI-MS (m/z): 589 [M+H]⁺.

Example 229:(S)-4′-((5-((1-(2,3-difluorophenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 8-9, Example 1, using the(S)-1-(2,3-difluorophenyl)ethanamine hydrochloride and the1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. ESI-MS (m/z): 539 [M+H]⁺.

Example 230:(S)-4′-((5-((1-(2-Chloro-3-(trifluoromethyl)phenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 8-9, Example 1, using the(S)-1-(2-chloro-3-(trifluoromethyl)phenyl)ethanamine hydrochloride andthe1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. ESI-MS (m/z): 605 [M+H]⁺.

Example 231:(R)-4′-((5-((1-(2-chloro-3-(trifluoromethyl)phenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 8-9, Example 1, using the(R)-1-(2-chloro-3-(trifluoromethyl)phenyl)ethanamine hydrochloride andthe1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. ESI-MS (m/z): 605 [M+H]⁺.

Example 232:(S)-4′-((5-((1-(3-chloro-2-fluorophenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 8-9, Example 1, using(S)-1-(3-chloro-2-fluorophenyl)ethanamine hydrochloride and the1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. ESI-MS (m/z): 555 [M+H]⁺.

Example 233:(S)-4′-((5-((1-(3,4-difluorophenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 8-9, Example 1, using the(S)-1-(3,4-difluorophenyl)ethanamine hydrochloride and the1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. ESI-MS (m/z): 539 [M+H]⁺.

Example 234:(R)-4′-((5-((1-(3-fluoro-4-(trifluoromethyl)phenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 8-9, Example 1, using the(R)-1-(3-fluoro-4-(trifluoromethyl)phenyl)ethanamine hydrochloride andthe1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. ESI-MS (m/z): 589 [M+H]⁺.

Example 235:(R)-4′-((2,3-dimethyl-5-((1-(2,3,6-trifluorophenyl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 8-9, Example 1, using the(R)-1-(2,3,6-trifluorophenyl)ethanamine hydrochloride and the1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. ESI-MS (m/z): 557 [M+H]⁺.

Example 236:(S)-4′-((2,3-dimethyl-5-((1-(2,3,6-trifluorophenyl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 8-9, Example 1, using the(S)-1-(2,3,6-trifluorophenyl)ethanamine hydrochloride and the1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. ESI-MS (m/z): 557 [M+H]⁺.

Example 237:4′-((5-(((S)-1-((S)-1-((benzyloxy)carbonyl)pyrrolidin-2-yl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 8-9, Example 1, using the (S)-benzyl2-((S)-1-aminoethyl)pyrrolidine-1-carboxylate hydrochloride and the1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. ESI-MS (m/z): 630 [M+H]⁺.

Example 238:4′-((5-(((S)-1-((R)-1-((benzyloxy)carbonyl)pyrrolidin-2-yl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 8-9, Example 1, using the (R)-benzyl2-((S)-1-aminoethyl)pyrrolidine-1-carboxylate hydrochloride and the1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. ESI-MS (m/z): 630 [M+H]⁺.

Example 239:(R)-4′-((5-((1-(5-fluoro-2-(trifluoromethyl)phenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 8-9, Example 1, using the(R)-1-(5-fluoro-2-(trifluoromethyl)phenyl)ethanamine hydrochloride andthe1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. ESI-MS (m/z): 589 [M+H]⁺.

Example 240:4′-((5-(((S)-1-((R)-1-((benzyloxy)carbonyl)pyrrolidin-3-yl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 8-9, Example 1, using the (R)-benzyl3-((S)-1-aminoethyl)pyrrolidine-1-carboxylate hydrochloride and the1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. ESI-MS (m/z): 630 [M+H]⁺.

Example 241:(S)-4′-((5-((1-(5-fluoro-2-(trifluoromethyl)phenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 8-9, Example 1, using the(S)-1-(5-fluoro-2-(trifluoromethyl)phenyl)ethanamine hydrochloride andthe1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. ESI-MS (m/z): 589 [M+H]⁺.

Example 242:(S)-1-((2′-cyano-[1,1′-biphenyl]-4-yl)methyl)-N-(1-(3-isopropylphenyl)ethyl)-2,3-dimethyl-1H-indole-5-carboxamide

The title compound was prepared following the same general protocol asdescribed in Step 8-9, Example 1, using the(S)-1-(5-fluoro-2-(trifluoromethyl)phenyl)ethanamine hydrochloride andthe 4′-(bromomethyl)-[1,1′-biphenyl]-2-carbonitrile. ESI-MS (m/z): 526[M+H]⁺.

Example 243:(S)-1-((2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-N-(1-(3-isopropylphenyl)ethyl)-2,3-dimethyl-1H-indole-5-carboxamide

The mixture of(S)-1-((2′-cyano-[1,1′-biphenyl]-4-yl)methyl)-N-(1-(3-isopropylphenyl)ethyl)-2,3-dimethyl-1H-indole-5-carboxamide(0.1 g, 0.19 mmol), azidotrimethylsilane 90.05 mL, 0.38 mmol) anddibutylstannanone (0.005 g, 0.019 mmol) in toluene (3 mL) was heated at110° C. oil bath for 16 hr. The solvent was removed and the residue waspurified by preparative-HPLC to obtain the title compound. ESI-MS (m/z):569 [M+H]⁺.

Example 244:(S)—N-(1-(3-isopropylphenyl)ethyl)-2,3-dimethyl-1-((2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-[1,1′-biphenyl]-4-yl)methyl)-1H-indole-5-carboxamide

A mixture of hydroxylammoium chloride (0.2 g, 2.88 mmol), sodiumhydrogen carbonate (0.3 g, 3.57 mmol) and dimethyl sulfoxide (2 mL) wasstirred at 40° C. for 30 min.(S)-1-((2′-cyano-[1,1′-biphenyl]-4-yl)methyl)-N-(1-(3-isopropylphenyl)ethyl)-2,3-dimethyl-1H-indole-5-carboxamide(0.1 g, 0.19 mmol) was added, and the mixture was stirred at 90° C. for16 hr. The reaction mixture was diluted with ethyl acetate, washed withwater and then with brine, and dried over anhydrous sodium sulfate.Thvent was evaporated under reduced pressure, and the residue wasdissolved in THF (3 mL), N, N′-carbonyldiimidazole (0.055 g, 0.29 mmol)and then 1,8-diazabicyclo[5,4,0] undec-7-ene (0.05 mL, 0.29 mmol) wereadded, and the mixture was stirred at room temperature for 2 hr. Thereaction mixture was diluted with ethyl acetate, washed with saturatedaqueous potassium hydrogensulfate solution and then with brine, anddried over anhydrous sodium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by preparative-HPLC toobtain the title compound. ESI-MS (m/z): 585 [M+H]⁺.

Example 245:(S)—N-(1-(3-isopropylphenyl)ethyl)-2,3-dimethyl-1-((2′-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-[1,1′-biphenyl]-4-yl)methyl)-1H-indole-5-carboxamide

Step 1:(S)-1-((2′-(hydrazinecarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-N-(1-(3-isopropylphenyl)ethyl)-2,3-dimethyl-1H-indole-5-carboxamide

To the mixture of(S)-4′-((5-((1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicacid (0.11 g, 0.201 mmol), hydrazine hydrochloride (0.028 g, 0.402 mmol)and HATU (0.092 g, 0.24 mmol) in DCM (2 mL) was added DIEA (0.14 mL, 0.8mmol). The mixture was stirred at room temperature for 16 h. The solventwas removed and the residue was purified by silica gel to obtain thetitle compound. ESI-MS (m/z): 559 [M+H]⁺.

Step 2:(S)—N-(1-(3-isopropylphenyl)ethyl)-2,3-dimethyl-1-((2′-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-[1,1′-biphenyl]-4-yl)methyl)-1H-indole-5-carboxamide

The mixture of(S)-1-((2′-(hydrazinecarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-N-(1-(3-isopropylphenyl)ethyl)-2,3-dimethyl-1H-indole-5-carboxamide(0.062 g, 0.11 mmol), N,N′-carbonyldiimidazole (0.027 g, 0.16 mmol) andDIEA (0.03 mL, 0.16 mmol) in DMF was stirred at room temperature for 1h, and then stirred at 50° C. for 1 h. The reaction mixture was pouredon to ice-water, and then extracted with ethyl acetate. The combinedorganic layers were washed with water and brine. Th solvent was removeand the residue was purified with preparative-HPLC to obtain the titlecompound. ESI-MS (m/z): 585 [M+H]⁺.

Example 246:(S)-1-((2′-(N-(tert-butyl)sulfamoyl)-[1,1′-biphenyl]-4-yl)methyl)-N-(1-(3-isopropylphenyl)ethyl)-2,3-dimethyl-1H-indole-5-carboxamide

Step 1: ethyl1-((2′-(N-(tert-butyl)sulfamoyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylate

The title compound was prepared following the same general protocol asdescribed in Step 6, Example 1, using the ethyl2,3-dimethyl-1H-indole-5-carboxylate and4′-(bromomethyl)-N-(tert-butyl)-[1,1′-biphenyl]-2-sulfonamide. ESI-MS(m/z): 519 [M+H]⁺.

Step 2:1-((2′-(N-(tert-butyl)sulfamoyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 7, Example 1, using the ethyl1-((2′-(N-(tert-butyl)sulfamoyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylate.ESI-MS (m/z): 491 [M+H]⁺.

Step 3:(S)-1-((2′-(N-(tert-butyl)sulfamoyl)-[1,1′-biphenyl]-4-yl)methyl)-N-(1-(3-isopropylphenyl)ethyl)-2,3-dimethyl-1H-indole-5-carboxamide

The title compound was prepared following the same general protocol asdescribed in Step 8, Example 1, using the(S)-1-(3-isopropylphenyl)ethanamine hydrochloride and1-((2′-(N-(tert-butyl)sulfamoyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. ESI-MS (m/z): 636 [M+H]⁺.

Example 247:(S)—N-(1-(3-isopropylphenyl)ethyl)-2,3-dimethyl-1-((2′-sulfamoyl-[1,1′-biphenyl]-4-yl)methyl)-1H-indole-5-carboxamide

The title compound was prepared following the same general protocol asdescribed in Step 9, Example 1, using the(S)-1-((2′-(N-(tert-butyl)sulfamoyl)-[1,1′-biphenyl]-4-yl)methyl)-N-(1-(3-isopropylphenyl)ethyl)-2,3-dimethyl-1H-indole-5-carboxamide.ESI-MS (m/z): 580 [M+H]⁺.

Example 248:(S)-1-((2′-(N-acetylsulfamoyl)-[1,1′-biphenyl]-4-yl)methyl)-N-(1-(3-isopropylphenyl)ethyl)-2,3-dimethyl-1H-indole-5-carboxamide

To the mixture of(S)—N-(1-(3-isopropylphenyl)ethyl)-2,3-dimethyl-1-((2′-sulfamoyl-[1,1′-biphenyl]-4-yl)methyl)-1H-indole-5-carboxamide(0.058 g, 0.1 mmol) and TEA (0.03 mL, 0.2 mmol) in DCM (0.5 mL) wasslowly added acetyl chloride (0.009 g, 0.11 mmol). The mixture wasstirred at room temperature for 1 h. The solvent was removed and theresidue was purified by preparative-HPLC to obtain the title compoundESI-MS (m/z): 622 [M+H]⁺.

Example 249:(R)-4′-((5-(chroman-3-ylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same protocol as describedin Step 8 and 9, Example 1, using (R)-chroman-3-amine instead of the(S)-1-(4-bromophenyl) ethanamine.

Example 250:(S)-4′-((5-(chroman-3-ylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same protocol as describedin Step 8 and 9, Example 1, using (S)-chroman-3-amine instead of the(S)-1-(4-bromophenyl) ethanamine.

Example 251:(S)-4′-((2,3-dimethyl-5-(1-(4-propylphenyl)ethylcarbamoyl)-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

The title compound was prepared following the same protocol as describedin Step 8 and 9, Example 1, using (S)-1-(4-propylphenyl)ethanaminiumchloride instead of the (S)-1-(4-bromophenyl)ethanamine. ESI-MS (m/z):545 [M+H]⁺.

Example 252:(S)-4′-((2,3-dimethyl-5-(1-o-tolylethylcarbamoyl)-1H-indol-1-yl)methyl)biphenyl-2-carboxylic Acid

The title compound was prepared following the same protocol as describedin Step 8 and 9, Example 1, using (S)-1-(o-tolyl)ethanaminium chlorideinstead of the (S)-1-(4-bromophenyl)ethanamine. ESI-MS (m/z): 517[M+H]⁺.

Example 253:(S)-4′-((5-(1-(4-ethoxyphenyl)ethylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

The title compound was prepared following the same protocol as describedin Step 8 and 9, Example 1, using (S)-1-(4-ethoxyphenyl)ethanaminiumchloride instead of the (S)-1-(4-bromophenyl)ethanamine. ESI-MS (m/z):547 [M+H]⁺.

Example 254:(S)-4′-((5-(1-(2-bromophenyl)ethylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

The title compound was prepared following the same protocol as describedin Step 8 and 9, Example 1, using (S)-1-(2-bromophenyl)ethanaminiumchloride instead of the (S)-1-(4-bromophenyl)ethanamine. ESI-MS (m/z):581 [M+H]⁺.

Example 255:(S)-4′-((5-(1-(2-ethylphenyl)ethylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

The title compound was prepared following the same protocol as describedin Step 8 and 9, Example 1, using (S)-1-(2-ethylphenyl)ethanaminiumchloride instead of the (S)-1-(4-bromophenyl)ethanamine. ESI-MS (m/z):531 [M+H]⁺.

Example 256:(S)-4′-((2,3-dimethyl-5-(1-(2-(trifluoromethoxy)phenyl)ethylcarbamoyl)-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

The title compound was prepared following the same protocol as describedin Step 8 and 9, Example 1, using(S)-1-(2-(trifluoromethoxy)phenyl)ethanaminium chloride instead of the(S)-1-(4-bromophenyl)ethanamine. ESI-MS (m/z): 587 [M+H]⁺.

Example 257:(S)-4′-((5-(1-(2-isopropoxyphenyl)ethylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

The title compound was prepared following the same protocol as describedin Step 8 and 9, Example 1, using (S)-1-(2-isopropoxyphenyl)ethanaminiumchloride instead of the (S)-1-(4-bromophenyl)ethanamine. ESI-MS (m/z):561 [M+H]⁺.

Example 258:(S)-4′-((2,3-dimethyl-5-(1-(4-(methylsulfonyl)phenyl)ethylcarbamoyl)-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

The title compound was prepared following the same protocol as describedin Step 8 and 9, Example 1, using(S)-1-(4-(methylsulfonyl)phenyl)ethanaminium chloride instead of the(S)-1-(4-bromophenyl)ethanamine. ESI-MS (m/z): 581 [M+H]⁺.

Example 259:4′-((5-(1-(5-cyclopropylpyridin-3-yl)ethylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

Step 1: 1-(5-bromopyridin-3-yl)ethanaminium Chloride

The title compound was prepared following the same general protocol asdescribed in Step 1 and 2, Example 2, using 5-bromonicotinaldehydeinstead of 4-t-butylbenzaldehyde.

Step 2: tert-butyl4′-((5-((1-(5-bromopyridin-3-yl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylate

The title compound was prepared following the same general protocol asdescribed in Step 8, Example 1, using1-(5-bromopyridin-3-yl)ethanaminium chloride instead of(S)-1-(4-bromophenyl)ethanamine.

Step 3: tert-butyl4′-((5-((1-(5-cyclopropylpyridin-3-yl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylate

The title compound was prepared following the same general protocol asdescribed in Step 1, Example 261, using tert-butyl4′-((5-((1-(5-bromopyridin-3-yl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylateinstead of (S)-tert-butyl 4′-((5-((1-(5-bromopyridin-2-yl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylate.

Step 4:4′-((5-((1-(5-cyclopropylpyridin-3-yl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 9, Example 1. ESI-MS (m/z): 544 [M+H]⁺.

Example 260:(S)-4′-((5-((1-(5-bromopyridin-2-yl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

Step 1: (S)-1-(5-bromopyridin-2-yl)ethanaminium chloride

The title compound was prepared following the same general protocol asdescribed in Step 1 and 2, Example 2, using 5-bromopicolinaldehydeinstead of 4-t-butylbenzaldehyde.

Step 2: (S)-tert-butyl4′-((5-((1-(5-bromopyridin-2-yl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylate

The title compound was prepared following the same general protocol asdescribed in Step 8, Example 1, using(S)-1-(5-bromopyridin-2-yl)ethanaminium chloride instead of(S)-1-(4-bromophenyl)ethanamine.

Step 3:(S)-4′-((5-((1-(5-bromopyridin-2-yl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 9, Example 1. ESI-MS (m/z): 582 [M+H]⁺.

Example 261:(S)-4′-((5-((1-(5-cyclopropylpyridin-2-yl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

Step 1: (S)-tert-butyl4′-((5-((1-(5-cyclopropylpyridin-2-yl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylate

A high-pressure vial was filled with the (S)-tert-butyl4′-((5-((1-(5-bromopyridin-2-yl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylate(50 mg, 0.078 mmol), cyclopropylboronic acid (8 mg, 0.09 mmol, 1.2equiv), Pd(OAc)₂ (12 mg, 0.055 mmol, 0.7 equiv), (Cy)₃P (8.7 mg, 0.031mmol, 0.4 equiv), K₃PO₄ (49 mg, 0.23 mmol, 3 equiv), in toluene-water(10%). The reaction mixture was heated at 100° C. for 3 h undermicrowaves. The mixture was evaporated in vacuo to obtain the crudewhich was purified by prep. HPLC (MeOH/Acetonitrile/water) to obtain thetitle compound.

Step 2:(S)-4′-((5-((1-(5-cyclopropylpyridin-2-yl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 9, Example 1. ESI-MS (m/z): 544 [M+H]⁺.

Example 262:(S)-4′-((5-((1-(6-chloropyridin-3-yl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

Step 1: (S)-1-(6-chloropyridin-3-yl)ethanaminium Chloride

The title compound was prepared following the same general protocol asdescribed in Step 1 and 2, Example 2, using 6-chloronicotinaldehydeinstead of 4-t-butylbenzaldehyde.

Step 2: (S)-tert-butyl4′-((5-((1-(6-chloropyridin-3-yl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylate

The title compound was prepared following the same general protocol asdescribed in Step 8, Example 1, using(S)-1-(6-chloropyridin-3-yl)ethanaminium chloride instead of(S)-1-(4-bromophenyl)ethanamine.

Step 3:(S)-4′-((5-((1-(6-chloropyridin-3-yl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 9, Example 1. ESI-MS (m/z): 538 [M+H]⁺.

Example 263:(S)-4′-((5-((1-(6-cyclopropylpyridin-3-yl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

Step 1: (S)-tert-butyl4′-((5-((1-(6-cyclopropylpyridin-3-yl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylate

The title compound was prepared following the same general protocol asdescribed in Step 1, Example 261, using (S)-tert-butyl4′-((5-((1-(6-chloropyridin-3-yl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylateinstead of (S)-tert-butyl 4′-((5-((1-(5-bromopyridin-2-yl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylate.

Step 2:(S)-4′-((5-((1-(6-cyclopropylpyridin-3-yl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 9, Example 1. ESI-MS (m/z): 544 [M+H]⁺.

Example 264:(R)-4′-((5-((1-(6-cyclopropylpyridin-3-yl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

Step 1: (R)-1-(6-chloropyridin-3-yl)ethanaminium Chloride

The title compound was prepared following the same general protocol asdescribed in Step 1 and 2, Example 2, using 6-chloronicotinaldehydeinstead of 4-t-butylbenzaldehyde.

Step 2: (R)-tert-butyl4′-((5-((1-(6-chloropyridin-3-yl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylate

The title compound was prepared following the same general protocol asdescribed in Step 8, Example 1, using(R)-1-(6-chloropyridin-3-yl)ethanaminium chloride instead of(S)-1-(4-bromophenyl)ethanamine.

Step 3: (R)-tert-butyl4′-((5-((1-(6-cyclopropylpyridin-3-yl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylate

The title compound was prepared following the same general protocol asdescribed in Step 1, Example 261, using (R)-tert-butyl4′-((5-((1-(6-chloropyridin-3-yl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylateinstead of (S)-tert-butyl 4′-((5-((1-(5-bromopyridin-2-yl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylate.

Step 4:(R)-4′-((5-((1-(6-cyclopropylpyridin-3-yl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 9, Example 1. ESI-MS (m/z): 544 [M+H]⁺.

Example 265:(S)-4′-((5-((1-(4-chloropyridin-2-yl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

Step 1: (S)-1-(4-chloropyridin-2-yl)ethanaminium Chloride

The title compound was prepared following the same general protocol asdescribed in Step 1 and 2, Example 2, using 4-chloropicolinaldehydeinstead of 4-t-butylbenzaldehyde.

Step 2: (S)-tert-butyl4′-((5-((1-(4-chloropyridin-2-yl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylate

The title compound was prepared following the same general protocol asdescribed in Step 8, Example 1, using(S)-1-(4-chloropyridin-2-yl)ethanaminium chloride instead of(S)-1-(4-bromophenyl)ethanamine.

Step 3:(S)-4′-((5-((1-(4-chloropyridin-2-yl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 9, Example 1. ESI-MS (m/z): 538 [M+H]⁺.

Example 266:(S)-4′-((5-((1-(4-cyclopropylpyridin-2-yl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

Step 1: (S)-tert-butyl4′-((5-((1-(4-cyclopropylpyridin-2-yl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylate

The title compound was prepared following the same general protocol asdescribed in Step 1, Example 261, using (S)-tert-butyl4′-((5-((1-(4-chloropyridin-2-yl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylateinstead of (S)-tert-butyl 4′-((5-((1-(5-bromopyridin-2-yl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylate.

Step 2:(S)-4′-((5-((1-(4-cyclopropylpyridin-2-yl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 9, Example 1. ESI-MS (m/z): 544 [M+H]⁺.

Example 267:(S)-4′-((5-(1-(2-bromopyridin-4-yl)ethylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

Step 1: (S)-1-(2-bromopyridin-4-yl)ethanaminium Chloride

The title compound was prepared following the same general protocol asdescribed in Step 1 and 2, Example 2, using 2-bromoisonicotinaldehydeinstead of 4-t-butylbenzaldehyde.

Step 2: (S)-tert-butyl4′-((5-((1-(2-bromopyridin-4-yl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylate

The title compound was prepared following the same general protocol asdescribed in Step 8, Example 1, using(S)-1-(2-bromopyridin-4-yl)ethanaminium chloride instead of(S)-1-(4-bromophenyl)ethanamine.

Step 3:(S)-4′-((5-(1-(2-bromopyridin-4-yl)ethylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 9, Example 1. ESI-MS (m/z): 582 [M+H]⁺.

Example 268:(S)-4′-((5-(1-(2-cyclopropylpyridin-4-yl)ethylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

Step 1: (S)-tert-butyl4′-((5-((1-(2-cyclopropylpyridin-4-yl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylate

The title compound was prepared following the same general protocol asdescribed in Step 1, Example 261, using (S)-tert-butyl4′-((5-((1-(2-bromopyridin-4-yl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylateinstead of (S)-tert-butyl 4′-((5-((1-(5-bromopyridin-2-yl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylate.

Step 2:(S)-4′-((5-(1-(2-cyclopropylpyridin-4-yl)ethylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 9, Example 1. ESI-MS (m/z): 544 [M+H]⁺.

Example 269:(R)-4′-((5-(1-(2-bromopyridin-4-yl)ethylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

Step 1: (R)-1-(2-bromopyridin-4-yl)ethanaminium Chloride

The title compound was prepared following the same general protocol asdescribed in Step 1 and 2, Example 2, using 2-bromoisonicotinaldehydeinstead of 4-t-butylbenzaldehyde.

Step 2: (R)-tert-butyl4′-((5-((1-(2-bromopyridin-4-yl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylate

The title compound was prepared following the same general protocol asdescribed in Step 8, Example 1, using(R)-1-(2-bromopyridin-4-yl)ethanaminium chloride instead of(S)-1-(4-bromophenyl)ethanamine.

Step 3:(R)-4′-((5-(1-(2-bromopyridin-4-yl)ethylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 9, Example 1. ESI-MS (m/z): 582 [M+H]⁺.

Example 270:(R)-4′-((5-(1-(2-cyclopropylpyridin-4-yl)ethylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

Step 1: (R)-tert-butyl4′-((5-((1-(2-cyclopropylpyridin-4-yl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylate

The title compound was prepared following the same general protocol asdescribed in Step 1, Example 261, using (R)-tert-butyl4′-((5-((1-(2-bromopyridin-4-yl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylateinstead of (S)-tert-butyl 4′-((5-((1-(5-bromopyridin-2-yl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylate.

Step 2:(R)-4′-((5-(1-(2-cyclopropylpyridin-4-yl)ethylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 9, Example 1. ESI-MS (m/z): 544 [M+H]⁺.

Example 271:(R)-4′-((5-(1-(6-bromopyridin-2-yl)ethylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

Step 1: (R)-1-(6-bromopyridin-2-yl)ethanaminium Chloride

The title compound was prepared following the same general protocol asdescribed in Step 1 and 2, Example 2, using 6-bromopicolinaldehydeinstead of 4-t-butylbenzaldehyde.

Step 2: (R)-tert-butyl4′-((5-((1-(6-bromopyridin-2-yl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylate

The title compound was prepared following the same general protocol asdescribed in Step 8, Example 1, using(R)-1-(6-bromopyridin-2-yl)ethanaminium chloride instead of(S)-1-(4-bromophenyl)ethanamine.

Step 3:(R)-4′-((5-(1-(6-bromopyridin-2-yl)ethylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 9, Example 1. ESI-MS (m/z): 582 [M+H]⁺.

Example 272:4′-((5-(1-(6-cyclopropylpyridin-2-yl)ethylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

Step 1: 1-(6-bromopyridin-2-yl)ethanaminium Chloride

The title compound was prepared following the same general protocol asdescribed in Step 1 and 2, Example 2, using 6-bromopicolinaldehydeinstead of 4-t-butylbenzaldehyde.

Step 2: tert-butyl4′-((5-((1-(6-bromopyridin-2-yl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylate

The title compound was prepared following the same general protocol asdescribed in Step 8, Example 1, using(R)-1-(6-chloropyridin-3-yl)ethanaminium chloride instead of(S)-1-(4-bromophenyl)ethanamine.

Step 3: tert-butyl4′-((5-((1-(6-cyclopropylpyridin-2-yl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylate

The title compound was prepared following the same general protocol asdescribed in Step 1, Example 261, using tert-butyl4′-((5-((1-(6-bromopyridin-2-yl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylateinstead of (S)-tert-butyl 4′-((5-((1-(5-bromopyridin-2-yl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylate.

Step 4:4′-((5-((1-(6-cyclopropylpyridin-2-yl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 9, Example 1. ESI-MS (m/z): 544 [M+H]⁺.

Example 273:(S)-4′-((5-(1-(6-bromopyridin-2-yl)ethylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

Step 1: (S)-1-(6-bromopyridin-2-yl)ethanaminium Chloride

The title compound was prepared following the same general protocol asdescribed in Step 1 and 2, Example 2, using 6-bromopicolinaldehydeinstead of 4-t-butylbenzaldehyde.

Step 2: (S)-tert-butyl4′-((5-((1-(6-bromopyridin-2-yl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylate

The title compound was prepared following the same general protocol asdescribed in Step 8, Example 1, using(S)-1-(6-bromopyridin-2-yl)ethanaminium chloride instead of(S)-1-(4-bromophenyl)ethanamine.

Step 3:(S)-4′-((5-(1-(6-bromopyridin-2-yl)ethylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 9, Example 1. ESI-MS (m/z): 582 [M+H]⁺.

Example 274:(S)-4′-((5-(1-(6-cyclopropylpyridin-2-yl)ethylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

Step 1: (S)-tert-butyl4′-((5-((1-(6-cyclopropylpyridin-2-yl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylate

The title compound was prepared following the same general protocol asdescribed in Step 1, Example 261, using (S)-tert-butyl4′-((5-((1-(6-bromopyridin-2-yl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylateinstead of (S)-tert-butyl 4′-((5-((1-(5-bromopyridin-2-yl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylate.

Step 2:(S)-4′-((5-(1-(6-cyclopropylpyridin-2-yl)ethylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 9, Example 1. ESI-MS (m/z): 544 [M+H]⁺.

Example 275:4′-((5-(1-(5-bromopyridin-3-yl)ethylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

Step 1: 1-(5-bromopyridin-3-yl)ethanaminium Chloride

The title compound was prepared following the same general protocol asdescribed in Step 1 and 2, Example 2, using 5-bromonicotinaldehydeinstead of 4-t-butylbenzaldehyde.

Step 2: tert-butyl4′-((5-((1-(5-bromopyridin-3-yl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylate

The title compound was prepared following the same general protocol asdescribed in Step 8, Example 1, using1-(5-bromopyridin-3-yl)ethanaminium chloride instead of(S)-1-(4-bromophenyl)ethanamine.

Step 3:4′-((5-(1-(5-bromopyridin-3-yl)ethylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 9, Example 1. ESI-MS (m/z): 582 [M+H]⁺.

Example 276:(R)-4′-((2,3-dimethyl-5-(1-(4-(methylsulfonyl)phenyl)ethylcarbamoyl)-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

Step 1: (R)-1-(4-(methylsulfonyl)phenyl)ethanaminium Chloride

The title compound was prepared following the same general protocol asdescribed in Step 1 and 2, Example 2, using4-(methylsulfonyl)benzaldehyde instead of 4-t-butylbenzaldehyde.

Step 2: (R)-tert-butyl4′-((2,3-dimethyl-5-((1-(4-(methylsulfonyl)phenyl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylate

The title compound was prepared following the same general protocol asdescribed in Step 8, Example 1, using(R)-1-(4-(methylsulfonyl)phenyl)ethanaminium chloride instead of(S)-1-(4-bromophenyl)ethanamine.

Step 3:(R)-4′-((2,3-dimethyl-5-(1-(4-(methylsulfonyl)phenyl)ethylcarbamoyl)-1H-indol-1-yl)methyl)biphenyl-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 9, Example 1. ESI-MS (m/z): 581 [M+H]⁺.

Example 277:(S)-1-((2′-cyano-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-N-(1-(4-(trifluoromethyl)phenyl)ethyl)-1H-indole-5-carboxamide

The title compound was prepared following the same protocol as describedin Step 5, Example 34, using (S)-1-(4-(trifluoromethyl)phenyl)ethanamineinstead of the 1-phenyl propan-1-amine. ESI-MS (m/z): 552 [M+H]⁺.

Example 278:(S)-1-((2′-cyano-[1,1′-biphenyl]-4-yl)methyl)-N-(1-(4-isopropoxyphenyl)ethyl)-2,3-dimethyl-1H-indole-5-carboxamide

The title compound was prepared following the same protocol as describedin Step 5, Example 34, using (S)-1-(4-isopropoxyphenyl)ethanamineinstead of the 1-phenyl propan-1-amine. ESI-MS (m/z): 542 [M+H]⁺.

Example 279:(S)-1-((2′-cyano-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)-1H-indole-5-carboxamide

The title compound was prepared following the same protocol as describedin Step 5, Example 34, using(S)-1-(4-(trifluoromethoxy)phenyl)ethanamine instead of the 1-phenylpropan-1-amine. ESI-MS (m/z): 568 [M+H]⁺.

Example 280:(S)-1-((2′-cyano-[1,1′-biphenyl]-4-yl)methyl)-N-(1-(3-ethoxyphenyl)ethyl)-2,3-dimethyl-1H-indole-5-carboxamide

The title compound was prepared following the same protocol as describedin Step 5, Example 34, using (S)-1-(3-ethoxyphenyl)ethanamine instead ofthe 1-phenyl propan-1-amine. ESI-MS (m/z): 528 [M+H]⁺.

Example 281:(S)—N-(1-(3-chlorophenyl)ethyl)-1-((2′-cyano-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxamide

The title compound was prepared following the same protocol as describedin Step 5, Example 34, using (S)-1-(3-chlorophenyl)ethanamine instead ofthe 1-phenyl propan-1-amine. ESI-MS (m/z): 518 [M+H]⁺.

Example 282:(S)-1-((2′-cyano-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-N-(1-(3-(trifluoromethyl)phenyl)ethyl)-1H-indole-5-carboxamide

The title compound was prepared following the same protocol as describedin Step 5, Example 34, using (S)-1-(3-(trifluoromethyl)phenyl)ethanamineinstead of the 1-phenyl propan-1-amine. ESI-MS (m/z): 552 [M+H]⁺.

Example 283:(S)—N-(1-(4-chlorophenyl)ethyl)-1-((2′-cyano-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxamide

The title compound was prepared following the same protocol as describedin Step 5, Example 34, using (S)-1-(4-chlorophenyl)ethanamine instead ofthe 1-phenyl propan-1-amine. ESI-MS (m/z): 518 [M+H]⁺.

Example 284:(S)—N-(1-(3-bromophenyl)ethyl)-1-((2′-cyano-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxamide

The title compound was prepared following the same protocol as describedin Step 5, Example 34, using (S)-1-(3-bromophenyl)ethanamine instead ofthe 1-phenyl propan-1-amine. ESI-MS (m/z): 562 [M+H]⁺.

Example 285:(S)-1-((2′-cyano-[1,1′-biphenyl]-4-yl)methyl)-N-(1-(4-methoxyphenyl)ethyl)-2,3-dimethyl-1H-indole-5-carboxamide

The title compound was prepared following the same protocol as describedin Step 5, Example 34, using (S)-1-(4-methoxyphenyl)ethanamine insteadof the 1-phenyl propan-1-amine. ESI-MS (m/z): 514 [M+H]⁺.

Example 286:(S)-1-((2′-cyano-[1,1′-biphenyl]-4-yl)methyl)-N-(1-(2,4-difluorophenyl)ethyl)-2,3-dimethyl-1H-indole-5-carboxamide

The title compound was prepared following the same protocol as describedin Step 5, Example 34, using (S)-1-(2,4-difluorophenyl)ethanamineinstead of the 1-phenyl propan-1-amine. ESI-MS (m/z): 520 [M+H]⁺.

Example 287:(S)—N-(1-(2-chlorophenyl)ethyl)-1-((2′-cyano-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxamide

The title compound was prepared following the same protocol as describedin Step 5, Example 34, using (S)-1-(2-chlorophenyl)ethanamine instead ofthe 1-phenyl propan-1-amine. ESI-MS (m/z): 518 [M+H]⁺.

Example 288:(S)-1-((2′-cyano-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-N-(1-(p-tolyl)ethyl)-1H-indole-5-carboxamide

The title compound was prepared following the same protocol as describedin Step 5, Example 34, using (S)-1-(4-methylphenyl)ethanamine instead ofthe 1-phenyl propan-1-amine. ESI-MS (m/z): 498 [M+H]⁺.

Example 289:(S)-1-((2′-cyano-[1,1′-biphenyl]-4-yl)methyl)-N-(1-(4-ethylphenyl)ethyl)-2,3-dimethyl-1H-indole-5-carboxamide

The title compound was prepared following the same protocol as describedin Step 5, Example 34, using (S)-1-(4-ethylphenyl)ethanamine instead ofthe 1-phenyl propan-1-amine. ESI-MS (m/z): 512 [M+H]⁺.

Example 290:(S)-1-((2′-cyano-[1,1′-biphenyl]-4-yl)methyl)-N-(1-(3,4-dichlorophenyl)ethyl)-2,3-dimethyl-1H-indole-5-carboxamide

The title compound was prepared following the same protocol as describedin Step 5, Example 34, using (S)-1-(3,4-dichlorophenyl)ethanamineinstead of the 1-phenyl propan-1-amine. ESI-MS (m/z): 552 [M+H]⁺.

Example 291:(S)-1-((2′-cyano-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-N-(1-phenylethyl)-1H-indole-5-carboxamide

The title compound was prepared following the same protocol as describedin Step 5, Example 34, using (S)-1-phenylethanamine instead of the1-phenyl propan-1-amine. ESI-MS (m/z): 484 [M+H]⁺.

Example 292:(S)-1-((2′-cyano-[1,1′-biphenyl]-4-yl)methyl)-N-(1-(2-methoxyphenyl)ethyl)-2,3-dimethyl-1H-indole-5-carboxamide

The title compound was prepared following the same protocol as describedin Step 5, Example 34, using (S)-1-(2-methoxyphenyl)ethanamine insteadof the 1-phenyl propan-1-amine. ESI-MS (m/z): 514 [M+H]⁺.

Example 293:(S)-1-((2′-cyano-[1,1′-biphenyl]-4-yl)methyl)-N-(1-(3-fluorophenyl)ethyl)-2,3-dimethyl-1H-indole-5-carboxamide

The title compound was prepared following the same protocol as describedin Step 5, Example 34, using (S)-1-(3-fluorophenyl)ethanamine instead ofthe 1-phenyl propan-1-amine. ESI-MS (m/z): 502 [M+H]⁺.

Example 294:4′-((2,3-Dimethyl-5-(((1R,2S)-2-phenylcyclopropyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 8-9, Example 1, using (1R,2S)-2-phenylcyclopropanaminehydrochloride and1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylicacid. ESI-MS (m/z): 515 [M+H]⁺.

Example 295:(S)-4′-((2,3-Dimethyl-5-((1-(m-tolyl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

Step 1: (S)-tert-Butyl4′-((2,3-dimethyl-5-((1-(m-tolyl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylate

A mixture of (S)-tert-butyl4′-((5-((1-(3-bromophenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylate(24 mg, 0.038 mmol), trimethylboroxine (10 mL, 0.072 mmol), Pd(PPh₃)₄(11 mg, 0.0095 mmol) and K₂CO₃ (15 mg, 0.11 mmol) in Dioxane (0.7 ml)were heated in a Biotage Microwave reactor at 100° C. for 2 h. Thesolvent was removed and the residue was purified by reverse phaseprep-HPLC (MeOH/Acetonitrile/water) to obtain the title compound.

Step 2:(S)-4′-((2,3-Dimethyl-5-((1-(m-tolyl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 9, Example 1. ESI-MS (m/z): 517 [M+H]⁺.

Example 296:(R)-4′-((5-((1-(3-Bromophenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

Step 1: (R)-tert-Butyl4′-((5-((1-(3-bromophenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylate

The title compound was prepared following the same general protocol asdescribed in Step 8, Example 1, using (R)-1-(3-bromophenyl)ethanamineinstead of (S)-1-(4-bromophenyl)ethanamine.

Step 2:(R)-4′-((5-((1-(3-Bromophenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 9, Example 1. ESI-MS (m/z): 581/583 [M+H]⁺.

Example 297:(S)-4′-((5-((1-(3-Cyclopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

Step 1: (S)-tert-Butyl4′-((5-((1-(3-cyclopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylate

A mixture of (S)-tert-butyl4′-((5-((1-(3-bromophenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylate(24 mg, 0.038 mmol), cyclopropylboronic acid (7 mg, 0.081 mmol),Palladium(II) acetate (3.5 mg, 0.016 mmol) tricyclohexylphosphine (9 mg,0.032 mmol) and potassium phosphate, tribasic, (23 mg, 0.11 mmol) intoluene (0.7 mL) and water (0.07 mL) was heated at 100° C. for 1 h in aBiotage Microwave reactor. The solvent was removed; the residue wasfiltered and purified by preparative HPLC to yield the title compound asa white solid.

Step 2:(S)-4′-((5-((1-(3-Cyclopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 9, Example 1. ESI-MS (m/z): 543 [M+H]⁺.

Example 298:(S)-4′-((5-((1-(2-Fluoro-4-(trifluoromethyl)phenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

Step 1: (S)-tert-Butyl4′-((5-((1-(2-fluoro-4-(trifluoromethyl)phenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylate

The title compound was prepared following the same general protocol asdescribed in Step 8, Example 1, using(S)-1-(2-fluoro-4-(trifluoromethyl)phenyl)ethanamine instead of(S)-1-(4-bromophenyl)ethanamine.

Step 2:(S)-4′-((5-((1-(2-Fluoro-4-(trifluoromethyl)phenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 9, Example 1. ESI-MS (m/z): 589 [M+H]⁺.

Example 299:(S)-4′-((5-((1-(2-Fluoro-3-(trifluoromethyl)phenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

Step 1: (S)-tert-Butyl4′-((5-((1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylate

The title compound was prepared following the same general protocol asdescribed in Step 8, Example 1, using(S)-1-(2-fluoro-3-(trifluoromethyl)phenyl)ethanamine instead of(S)-1-(4-bromophenyl)ethanamine.

Step 2:(S)-4′-((5-((1-(2-Fluoro-3-(trifluoromethyl)phenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 9, Example 1. ESI-MS (m/z): 589 [M+H]⁺.

Example 300:(S)-4′-((5-((1-(2-Fluoro-6-(trifluoromethyl)phenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

Step 1: (S)-tert-Butyl4′-((5-((1-(2-fluoro-6-(trifluoromethyl)phenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylate

The title compound was prepared following the same general protocol asdescribed in Step 8, Example 1, using(S)-1-(2-fluoro-6-(trifluoromethyl)phenyl)ethanamine instead of(S)-1-(4-bromophenyl)ethanamine.

Step 2:(S)-4′-((5-((1-(2-Fluoro-6-(trifluoromethyl)phenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 9, Example 1. ESI-MS (m/z): 589 [M+H]⁺.

Example 301:(S)-4′-((2,3-Dimethyl-5-((1-(2,4,5-trifluorophenyl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

Step 1: (S)-tert-Butyl4′-((2,3-dimethyl-5-((1-(2,4,5-trifluorophenyl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylate

The title compound was prepared following the same general protocol asdescribed in Step 8, Example 1, using(S)-1-(2,4,5-trifluorophenyl)ethanamine instead of(S)-1-(4-bromophenyl)ethanamine.

Step 2:(S)-4′-((2,3-Dimethyl-5-((1-(2,4,5-trifluorophenyl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 9, Example 1. ESI-MS (m/z): 557 [M+H]⁺.

Example 302:(S)-4′-((5-((1-(2-Chloro-5-(trifluoromethyl)phenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

Step 1: (S)-tert-butyl4′-((5-((1-(2-chloro-5-(trifluoromethyl)phenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylate

The title compound was prepared following the same general protocol asdescribed in Step 8, Example 1, using(S)-1-(2-chloro-5-(trifluoromethyl)phenyl)ethanamine instead of(S)-1-(4-bromophenyl)ethanamine.

Step 2:(S)-4′-((5-((1-(2-Chloro-5-(trifluoromethyl)phenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 9, Example 1. ESI-MS (m/z): 605 [M+H]⁺.

Example 303:(S)-4′-((5-((1-(2,4-Dichlorophenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

Step 1: (S)-tert-Butyl4′-((5-((1-(2,4-dichlorophenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylate

The title compound was prepared following the same general protocol asdescribed in Step 8, Example 1, using(S)-1-(2,4-dichlorophenyl)ethanamine instead of(S)-1-(4-bromophenyl)ethanamine.

Step 2:(S)-4′-((5-((1-(2,4-Dichlorophenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

The title compound was prepared following the same general protocol asdescribed in Step 9, Example 1. ESI-MS (m/z): 571 [M+H]⁺.

Example 304:(S)-4′-((5-((1-(4-Cyclopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicAcid

A mixture of(S)-4′-((5-((1-(4-bromophenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicacid (28 mg, 0.048 mmol), cyclopropylboronic acid (9 mg, 0.10 mmol),Palladium(II) acetate (3.9 mg, 0.017 mmol) tricyclohexylphosphine (10mg, 0.036 mmol) and potassium phosphate, tribasic, (22 mg, 0.10 mmol) intoluene (2.5 mL) and water (0.3 mL) was heated at 100° C. for 1 h in aBiotage Microwave reactor. The solvent was removed; the residue wasfiltered and purified by preparative HPLC to yield the title compound asa white solid. ESI-MS (m/z): 543 [M+H]⁺.

Example 305:(S)-1-((2′-(Cyclopropylcarbamoyl)-[1,1′-biphenyl]-4-yl)methyl)-N-(1-(3-isopropylphenyl)ethyl)-2,3-dimethyl-1H-indole-5-carboxamide

The title compound was prepared using the same general protocol asdescribed in Step 8, Example 1. ESI-MS (m/z): 584 [M+H]⁺.

Example 306:1-((2′-((8)-3-Hydroxypyrrolidine-1-carbonyl)-[1,1′-biphenyl]-4-yl)methyl)-N—((S)-1-(3-isopropylphenyl)ethyl)-2,3-dimethyl-1H-indole-5-carboxamide

The title compound was prepared using the same general protocol asdescribed in Step 8, Example 1. ESI-MS (m/z): 614 [M+H]⁺.

Example 307:(S)-1-((2′-((2-Hydroxyethyl)carbamoyl)-[1,1′-biphenyl]-4-yl)methyl)-N-(1-(3-isopropylphenyl)ethyl)-2,3-dimethyl-1H-indole-5-carboxamide

The title compound was prepared using the same general protocol asdescribed in Step 8, Example 1. ESI-MS (m/z): 588 [M+H]⁺.

Example 308:(S)-1-((2′-(Cyclohexylcarbamoyl)-[1,1′-biphenyl]-4-yl)methyl)-N-(1-(3-isopropylphenyl)ethyl)-2,3-dimethyl-1H-indole-5-carboxamide

The title compound was prepared using the same general protocol asdescribed in Step 8, Example 1. ESI-MS (m/z): 626 [M+H]⁺.

Example 309:1-((2′-(((R)-3-(Dimethylamino)-2-hydroxy-3-oxopropyl)carbamoyl)-[1,1′-biphenyl]-4-yl)methyl)-N—((S)-1-(3-isopropylphenyl)ethyl)-2,3-dimethyl-1H-indole-5-carboxamide

The title compound was prepared using the same general protocol asdescribed in Step 8, Example 1. ESI-MS (m/z): 659 [M+H]⁺.

Example 310:(S)-1-((2′-((2-(Dimethylamino)ethyl)carbamoyl)-[1,1′-biphenyl]-4-yl)methyl)-N-(1-(3-isopropylphenyl)ethyl)-2,3-dimethyl-1H-indole-5-carboxamide

The title compound was prepared using the same general protocol asdescribed in Step 8, Example 1. The TFA salt of the title compound wasobtained. ESI-MS (m/z): 615 [M+H]⁺.

Example 311:(S)—N-(1-(3-Isopropylphenyl)ethyl)-2,3-dimethyl-1-((2′-(methylcarbamoyl)-[1,1′-biphenyl]-4-yl)methyl)-1H-indole-5-carboxamide

The title compound was prepared using the same general protocol asdescribed in Step 8, Example 1. ESI-MS (m/z): 558 [M+H]⁺.

Example 312:(S)-1-((2′-(Dimethylcarbamoyl)-[1,1′-biphenyl]-4-yl)methyl)-N-(1-(3-isopropylphenyl)ethyl)-2,3-dimethyl-1H-indole-5-carboxamide

The title compound was prepared using the same general protocol asdescribed in Step 8, Example 1. ESI-MS (m/z): 572 [M+H]⁺.

Example 313:((S)-1-((2′-(Hydroxycarbamoyl)-[1,1′-biphenyl]-4-yl)methyl)-N-(1-(3-isopropylphenyl)ethyl)-2,3-dimethyl-1H-indole-5-carboxamide

Step 1:(S)-1-((2′-(((tert-Butyldimethylsilyl)oxy)carbamoyl)-[1,1′-biphenyl]-4-yl)methyl)-N-(1-(3-isopropylphenyl)ethyl)-2,3-dimethyl-1H-indole-5-carboxamide

The title compound was prepared using the same general protocol asdescribed in Step 8, Example 1.

Step 2:((S)-1-((2′-(Hydroxycarbamoyl)-[1,1′-biphenyl]-4-yl)methyl)-N-(1-(3-isopropylphenyl)ethyl)-2,3-dimethyl-1H-indole-5-carboxamide

The solution of(S)-1-((2′-(((tert-Butyldimethylsilyl)oxy)carbamoyl)-[1,1′-biphenyl]-4-yl)methyl)-N-(1-(3-isopropylphenyl)ethyl)-2,3-dimethyl-1H-indole-5-carboxamidein DCM (3 mL) and TFA (0.5 mL) was stirred for 1 h at rt. The solventwas removed and the residue was purified by reverse phase prep-HPLC(MeOH/Acetonitrile/water) to obtain the title compound. ESI-MS (m/z):560 [M+H]⁺.

Example 314:(S)—N-(1-(3-Isopropylphenyl)ethyl)-2,3-dimethyl-1-((2′-((methylsulfonyl)carbamoyl)-[1,1′-biphenyl]-4-yl)methyl)-1H-indole-5-carboxamide

The mixture of(S)-4′-((5-((1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylicacid (30 mg, 0.055 mmol), methanesulfonamide (15 mg, 0.16 mmol), EDAC(25 mg, 0.13 mmol) and DMAP (26 mg, 0.21 mmol) in DMF (3 mL) was stirredat rt for 15 h. The solvent was removed and the residue was purified byreverse phase prep-HPLC (MeOH/Acetonitrile/water) to obtain the titlecompound. ESI-MS (m/z): 622 [M+H]⁺.

Example 315:(S)-1-((2′-Carbamoyl-[1,1′-biphenyl]-4-yl)methyl)-N-(1-(3-isopropylphenyl)ethyl)-2,3-dimethyl-1H-indole-5-carboxamide

The title compound was prepared using the same general protocol asdescribed in Step 8, Example 1. ESI-MS (m/z): 544 [M+H]⁺.

Bioassay Procedures Lanthascreen PPARG Competitive Binding Assay(Invitrogen)

The assay was performed according to manufacturer protocol. A mixture of5 nM GST-PPARG-LBD, 5 nM Tb-GST-antibody, 5 nM Fluormone Pan-PPAR Green,and serial dilutions of the experimental compound, beginning at 10 μMdownwards, was added to wells of black 384-well low-volume plates(Greiner) to a total volume of 18 μL. All dilutions were made in TR-FRETassay buffer C. DMSO at 2% final concentration was used as a no-ligandcontrol. Experiment was performed in triplicate, and incubated for 2hours in the dark prior to assay read in Perkin Elmer ViewLux ultra HTSmicroplate reader. FRET signal was measured by excitation at 340 nm andemission at 520 nm for fluorescein and 490 nm for terbium. Fold changeover DMSO was calculated using GraphPad Prism Software (La Jolla,Calif.) by calculating 520 nm/490 nm ratio. Graphs were plotted as foldchange of FRET signal for compound treatment over DMSO-only control.

Cell-Based Transactivation Assay:

PPRE is a DNA that contains a binding site for PPARG; thus PPRE is aPPAR response element, used herein as a promoter reporter. The bindingsite is a DR1 response element with the sequence AGGTCA repeated 3 timesin tandem and then fused to a construct for luciferase.

Thus, PPRE is the basis of the cell based transactivation assaydescribed below. The plasmid DNA is co-transfected along with a plasmidfor PPARG into COS-1 cells. After an overnight incubation, cells aretreated with DMSO or compounds. In this assay rosiglitazone activatesthe reporter about 5 fold. Partial agonists such as MRL24 transactivatethe reporter about 25% of rosiglitazone response. Compounds of theinvention which are non-activators afford no transactivation of thereporter.

Confluent COS-1 cells were transfected with 4.5 μg murine PPARg2-pSVSport or full-length human PPARg-pSport6, 4.5 μg 3×PPRE-luciferasereporter and 27 μL X-treme Gene 9 transfection reagent in serum-freeopti-mem media (Gibco), followed by overnight incubation at 37° C., 5%CO₂. Transfected cells were plated in white Perkin Elmer 384-well platesand incubated 4 hours. Cells were treated with DMSO vehicle only orexperimental compounds in increasing doses from 2 μM-220 pM for mousereceptor and 10 μM-111 fM for human. After 18 hour incubation, treatedcells were developed with Brite Lite Plus (Perkin Elmer) and read in384-well Luminescence Perkin Elmer EnVision Multilabel plate reader.Graphs were plotted in triplicate in GraphPad Prism Software as foldchange of treated cells over DMSO control cells. The human PPAR nuclearreceptor ligand binding domain (LBD) is fused to the DNA-Binding Domainof the yeast GAL4 transcription factor. The hybrid fusion-proteinnuclear receptor can activate the luciferase reporter under the controlof the GAL4 Upstream Activator Sequence (UAS).

The plasmid Gal4-PPAR DNA is co-transfected along with a plasmid forUAS-luc into HEK 293T cells. After an overnight incubation, cells aretreated with DMSO or compounds. In this assay rosiglitazone activatesthe reporter about 100-fold. Partial agonists transactivate the reporterabout 30-40% of rosiglitazone response. Compounds of the invention whichare non-activators exhibit <5% transactivation of the receptor at 1 mM.

HEK 293T cells were transfected with 4.5 μg of Gal4-PPARg, 4.5 μgUAS-luciferase reporter and 27 μL X-treme Gene 9 transfection reagent inserum-free opti-mem media (Gibco), followed by overnight incubation at37° C., 5% CO₂. Transfected cells were replated in white Perkin Elmer384-well plates and incubated 4 hours. Cells were treated with DMSOvehicle only or experimental compounds in doses from 10 μM-111 fM. After18 hour incubation, treated cells were developed with Brite Lite Plus(Perkin Elmer) and read in 384-well Luminescence Perkin Elmer EnVisionMultilabel plate reader. Graphs were plotted in triplicate in GraphPadPrism Software as fold change of treated cells over DMSO control cells.

Biodata Tables 1-5, below, provides biological data for the specificallyclaimed compounds as shown in Table 1, above, listing compound examplesof the invention covering almost all of compound examples 1-320. Eachline of Biodata Tables 1-5 represents biodata for the correspondingsingle compound of the set listed in Table 1, with respect to IC₅₀ asdetermined by the Lanthascreen procedure, and EC50 as determined by thecell-based transactivation assay. A compound with a relatively low IC50concentration is indicated to have potent PPARG binding activity,whereas a compound with a relatively high EC50 value in the cell-basedtransactivation assay is indicated to possess non-agonistic properties.In various embodiments, the invention provides compounds combining thesetwo properties, non-agonistic and PPARG binding.

Evaluations

It is within ordinary skill to evaluate any compound disclosed andclaimed herein for effectiveness in non-agonistic binding to PPARG andin the various cellular assays using the procedures described above orfound in the scientific literature. Accordingly, the person of ordinaryskill can prepare and evaluate any of the claimed compounds withoutundue experimentation.

Any compound found to be an effective non-agonist PPARG bindingmolecular entity can likewise be tested in animal models and in humanclinical studies using the skill and experience of the investigator toguide the selection of dosages and treatment regimens.

Example 316: Binding Affinities

The purpose of this example was to determine binding affinities (IC50)of inventive compounds as determined by the Lantha Screen displacementassay (n=3) described above. The following table shows affinities forselected compounds in comparison with rosiglitazone:

COMPOUND IC₅₀ Rosiglitazone 60 IB-72 (SR1663) 2 IB-73 (SR1664) 80 IB-2(SR2595) 30 IA-58 (SR10221) 15

Example 317: Pharmacokinetic Properties of Compounds of the Invention

The purpose of this example was to determine if pharmacological PPARγrepression would impair insulin sensitivity.

All animal experiments were performed according to procedures approvedby Scripps-Florida IACUC Committee. Male C57BL/6J mice were purchasedfrom the Jackson Laboratory (7-week-old) and fed a regular chow dietthrough experiments. The mice were dosed by oral gavage once daily with5 mg kg⁻¹ rosiglitazone or 20 mg kg⁻¹ Compound IB-2 (SR2595) for 21days. For insulin tolerance tests, mice were fasted overnight beforei.p. injection of 0.75 U/kg insulin (Sigma). Glucose was then measuredby tail vein bleeds at the indicated intervals using an OneTouch Ultra2glucometer. Plasma insulin concentration was determined by ELISA(Millipore mouse/rat insulin. cat #EZRMI-13K).

The results are shown in FIG. 12 , indicating that the pharmacokineticproperties of SR2595 were sufficient to support once daily oral dosingat 20 mg/kg.

Example 318: Increase of Bone Mass and Bone Formation

The purpose of this example is to demonstrate that the compounds of theinvention increase bone mass in pathological conditions of bone loss orto increase bone formation in conditions that compromise fracturehealing.

The compound IA-48 (SR10171) acts as an antagonist to PPARypro-adipocytic activity, and it has been further tested in vivo for itseffect on bone. SR10171 was administered to hyperglycemic C57BL/6 mice,12 wks old males, that were purchased from the Jackson Laboratories (BarHarbor, Me.). DIO mice: Animals were fed ad libitum for 11 wks high fatdiet (HFD) providing 45 kcal % from fat (D12451; Research Diets, NewBrunswick, N.J.) to develop diet induced obesity (DIO).

DIO mice were separated into three groups (n=8) and fed for 4 wks asfollows: HFD (control), HFD supplemented with rosiglitazone at the dose25 mg/kg/d, and HFD supplemented with SR10171 at the dose 25 mg/kg/d.The dose of SR10171 was calculated based on the following reasoning:SR10171 binding affinity to PPARy is 10-fold lower and its 5273phosphorylation blocking activity is 50% lower than rosiglitazone. Thistogether with 2.5-fold higher than rosiglitazone retention levels inplasma of animals treated for 4 days resulted in the decision to treatanimals with the same dose of each drug. The exact amount was decidedbased on our experience that a dose of rosiglitazone between 20-25mg/kg/day administered for 4 weeks to DIO animals results in significantloss of trabecular bone in both, axial and appendicular skeleton (Kolli,V., et al. Partial Agonist, Telmisartan, Maintains PPARgamma Serine 112Phosphorylation, and Does Not Affect Osteoblast Differentiation and BoneMass. PLoS One 9, e96323 (2014). Ingested doses of SR10171 (22 mg/kg/d)and rosiglitazone (24 mg/kg/d) were calculated at the end of treatmentbased on food intake monitored throughout duration of entire experiment.In parallel, a group of sex- and age-matched control (n=5) was fedregular diet (RD) providing 12 kcal % from fat (2016 Teklad Global,Harlan Laboratories, Indianapolis, Ind.). Second experiment wasconducted on 12 wks old males, lean C57BL/6 mice, which were fed for 8weeks either non-supplemented RD, or RD supplemented with rosiglitazone,or RD supplemented with SR10171. Food intake was monitored during theentire experiment to calculate an ingested dose of SR10171 (12.7mg/kg/d) and rosiglitazone (11.7 mg/kg/d). The animal treatment and careprotocols conformed to the NIH Guidelines and were performed under theUniversity of Toledo Health Science Campus Institutional Animal Care andUtilization Committee protocol.

Fat and lean mass were evaluated at the beginning and at the end ofexperiment using a Minispec mq10 NMR analyzer (Bruker, Billerica,Mass.). Glucose disposal (glucose tolerance test, GTT) was measuredafter ip injection of 2 g/kg glucose to animals fasted for 4 hrs. Bloodglucose was measured using the AlphaTRAK system appropriate for mice(Abbott Laboratories, North Chicago, Ill.). For indirect calorimetry,mice were evaluated in metabolic cages (CLAMS; Columbus Instruments,Columbus, Ohio) for 4 days with a free access to food and water. Micewere housed individually at room temperature (22 C) under an alternating12-h light/dark cycle. After one day adaptation, oxygen (VO2)consumption, carbon dioxide (VCO2) production, physical activity, andheat production were measured to determine energy expenditure.Respiratory exchange ratio was calculated as a ratio of the 02consumption and the CO₂ production.

The effect of SRI0171 on bone mass was compared to the effect ofrosiglitazone. At the end of experiment, bones (tibia, femur andvertebra) were isolated and their volume and microarchitecture wasanalyzed using micro-computed tomography.

Micro CT Imaging of Bone and Marrow Fat

mCT of the tibiae was performed using the μCT-35 system (Scanco MedicalAG, Bruettisellen, Switzerland) as previously described (Liu, L., et al.Rosiglitazone inhibits bone regeneration and causes significantaccumulation of fat at sites of new bone formation. Calcif Tissue Int91, 139-148 (2012). Briefly, scans were performed at 7 μm nominalresolution with the x-ray source operating at 70 kVp, and 113 μAsettings. Scans consisted of 300 slices starting at the growth plate ofproximal tibia and images of trabecular bone were segmented at 220threshold value using per mille scale following manual contouringstarting 10 slices below the growth plate and extending to the end ofthe image stack. Scans of cortical bone at tibia midshaft consisting of55 slices were obtained at 7 μm nominal resolution with the x-ray sourceoperating at 70 kVp and 113 μA. Images of cortical bone were contouredin the entire image stack and segmented at 260 threshold using per millescale. The analysis of the trabecular bone microstructure and thecortical bone parameters was conducted using Evaluation Program V6.5-1(Scanco Medical AG, Bruettisellen, Switzerland) and conformed torecommended guidelines (Bouxsein, M. L., et al. Guidelines forassessment of bone microstructure in rodents using micro-computedtomography. J Bone Miner Res 25, 1468-1486 (2010).

For lipid content evaluation, decalcified bone specimens were stainedfor 1 hr in solution containing 2% osmium tetroxide prepared in 0.1Msodium cacodylate buffer pH 7.4, according to the protocol (Liu et al.,2012). Staining was carried-out in an exhaust hood and away from lightdue to osmium tetroxide toxicity and light sensitivity. Images of lipiddepositions were acquired at 70 kVp and 113 μA settings and 12 μmnominal resolution. Image segmentation was done under global thresholdcondition by applying a threshold of 480-1000 using permille scale with3-dimensional noise filter set to sigma 1.2 and support 2.0. Lipidvolumes were calculated directly from individual voxel volumes in 3-Dreconstructions.

Bone Histomorphometry

To obtain static and dynamic bone histomorphometry, animals wereinjected with 2.5 mg/ml calcein solution in 2% sodium bicarbonate at adose 20 mg/kg body weight. First injection was performed 10 days andsecond 2 days before sacrifice. Undecalcified tibiae were embedded inmethyl methacrylate, sectioned and stained with either Golden Trichromeor Von Kossa/McNeal by Histology Core at the Department of Anatomy andCell Biology, Indiana University (Indianapolis, Ind.). Thehistomorphometric examination was confined to the secondary spongiosa ofproximal tibia and was performed using Nikon NIS-Elements BR3.1 system.The measurements were collected under 40× magnification from sixrepresentative fields per bone sample. The terminology and units usedwere those recommended by the Histomorphometry Nomenclature Committee ofthe American Society for Bone and Mineral Research (Parfitt, A. M., etal. Bone histomorphometry: standardization of nomenclature, symbols, andunits. Report of the ASBMR Histomorphometry Nomenclature Committee. JBone Miner Res 2, 595-610 (1987).

The measurements as described above showed that SR10171 compoundincreased bone mass and bone size and decreased bone marrow fat contentin bone region of trabecular structure.

In contrast, rosiglitazone at the same pharmacological dose decreasedtrabecular bone mass by 70% and significantly increased fat content inthe bone marrow. In addition, SR10171 increased overall bone size andbone area in midshaft tibia which contains cortical bone. These changesin the bone mass and bone geometry increased bone strength as measuredby calculating tortional strength and bone bending strength.

These findings show that compounds such as SR10171, which do not possessPPARγ transcriptional pro-adipocytic activity can exert a beneficialeffect on bone. The findings further indicate that the inventivecompounds can be used as bone anabolic drugs to increase bone mass inpathological conditions of bone loss, e.g. osteoporosis, or to increasebone formation in conditions that compromise fracture healing, e.g.diabetes.

In addition, the data showed that beneficial effects on bone areindependent of SR10171 metabolic activity. SR10171 increases energymetabolism and normalizes fat function in animals with diet inducedobesity, but unlike rosiglitazone it is neutral in animals with balancedenergy metabolism. Our data suggest that SR10171 modulates energymetabolism in an on-demand manner, while having sustained anabolicactivity on bone regardless of animal metabolic status.

In lean mice, SR10171 exerted a more robust positive effect on bone.Trabecular bone mass in proximal tibia was increased by 26% as comparedto non-treated animals, whereas animals receivingrosiglitazone-supplemented diet lost 30% of bone mass (FIG. 13 ). Theincrease in bone mass was due to increased number of trabeculae, but nottheir thickness (FIG. 13). In contrast to obese mice, lean mice treatedwith SR10171 did not experience effects on tibia cortical bone, neithercortical bone area nor cortical thickness.

What is claimed is:
 1. A method for treatment of a patient afflicted bya progressive bone disease, comprising administering to the patient aneffective dose of a compound of formula (I)

wherein: R is H, (C₁-C₆)alkyl, (C₃-C₉)cycloalkyl, or(C₃-C₉)cycloalkyl(C₁-C₆)alkyl; Y¹ or Y² are each independently C or N,provided that when Y¹ or Y² is N, le or R², respectively, is absent; R¹and R² are independently H, (C₁-C₆)alkyl, (C₃-C₉)cycloalkyl, or(C₁-C₆)haloalkyl; or R¹ and R² together with the atoms to which they arebonded form a 5- to 9-membered ring, comprising 0-3 heteroatoms selectedfrom the group consisting of O, NR, and SO_(q) wherein q is 0, 1, or 2,and optionally mono- or multi-substituted with independently selected(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₆-C₁₀)aryl,(C₃-C₉)cycloalkyl, halo, oxo, (C₁-C₆)haloalkyl, nitro,cyano-(C₀-C₆)alkyl, R′O₂C—(C₀-C₆)alkyl, methylenedioxy,R′O—(C₀-C₆)alkyl, (R′)₂N—(C₀-C₆)alkyl, (R′)₂NC(═O)—(C₀-C₆)alkyl,R′C(═O)N(R′)—(C₀-C₆)alkyl, (C₁-C₆)alkyl-S(O)_(q)(C₀-C₆)alkyl, aryl,aroyl, or SO₂NR′₂; R³ is optionally mono- or multi-substituted(C₁-C₆)alkyl, (C₁-C₆)alkenyl, (C₁-C₆)alkynyl, (C₆-C₁₀)aryl,(C₆-C₁₀)aryl(C₁-C₆)alkyl, (3-9 membered)heterocyclyl, (3-9membered)heterocyclyl(C₁-C₆)alkyl, (3-9 membered)heteroaryl, or (3-9membered)heteroaryl(C₁-C₆)alkyl; wherein if present each substituent onR³ is independently selected from the group consisting of (C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₆-C₁₀)aryl, (C₃-C₉)cycloalkyl, 3-9membered mono- and bicyclic heterocyclyl, 3-9 membered mono- andbicyclic heteroaryl, halo, oxo, haloalkyl, haloalkoxy, nitro, cyano,CO₂R′, methylenedioxy, OR′, N(R′)₂, C(O)N(R′)₂, (C₁-C₆)alkyl-S(O)_(q),SO₂NR′₂, and (C₁-C₆)alkoxyl; and provided that group R³N(R)C(═O)— can bebonded to any one of the four carbon atoms of the phenyl ring not bondedto N¹ or Y¹; wherein each R′ is independently H, (C₁-C₆) alkyl,(C₃-C₉)cycloalkyl, (C₃-C₉)cycloalkyl(C₁-C₆)alkyl, (C₆-C₁₀)aryl, or(C₆-C₁₀)aryl(C₁-C₆) alkyl, or wherein two R′ bonded to an atom togetherwith the atom form a 3-9 membered ring optionally further comprising aheteroatom selected from the group consisting of O, NR′, and S(O)_(q);wherein any alkyl, alkenyl, alkynyl, aryl, arylalkyl, or cycloalkyl ofR′ is optionally mono- or independently multi-substituted with(C₁-C₆)haloalkyl, (C₁-C₆)alkoxy, (C₁-C₆)haloalkoxy, halo, oxo, aryl, oraroyl; each of X¹-X⁵ is independently N or CH, or is C substituted withan independently selected R⁴ or is C substituted with Z, provided thatno more than two of X¹-X⁵ are N, and provided that there is no more thanone Z group bonded to the ring comprising X¹-X⁵; each R⁴ isindependently halo, nitro, (C₁-C₆)fluoroalkyl, R′—(C₀-C₆)alkyl,R′O₂C—(C₀-C₆)alkyl, NC—(C₀-C₆)alkyl, R′O—(C₀-C₆)alkyl,(R′)₂N—(C₀-C₆)alkyl, (R′)₂NC(═O)—(C₀-C₆)alkyl,R′C(═O)N(R′)—(C₀-C₆)alkyl, C-bonded tetrazolyl,3-hydroxypyrrolidin-1-carbonyl, 2-hydroxyethylaminocarbonyl,cyclohexylaminocarbonyl,2-(N,N-dimethylaminocarbonyl)-2-hydroxyethylaminocarbonyl,N,N-dimethylaminoethylcarbonyl, N-methylaminocarbonyl,N-hydroxylaminocarbonyl, (1,3,4-oxadiazol-2(3H)-on)-yl,(1,2,4-oxadiazol-5(4H)-on)-3-yl, (C₁-C₆)alkyl-S(O)_(q)(C₀-C₆)alkyl,R'S(O)₂NHC(O), R′C(O)NHS(O)₂, an unsubstituted or substituted aryl, anunsubstituted or substituted heteroaryl, (C₁-C₆)alkyl or(C₃-C₉)cycloalkyl-(C₀-C₆)alkyl, wherein any alkyl or cycloalkyl isoptionally mono- or independently multi-substituted with R′, OR′,N(R′)₂, C-bonded tetrazolyl, (C₁-C₆)alkyl-S(O)_(q)(C₀-C₆)alkyl, anunsubstituted or substituted aryl, or an unsubstituted or substitutedheteroaryl; or R⁴ is —(C(R″)₂)_(m)CO₂R′, —(C(R″)₂)_(m)CON(R′)₂,—(C(R″)₂)_(m)CN, —O(C(R″)₂)_(m)CO₂R′, —O(C(R″)₂)_(m)CON(R′)₂, or—O(C(R″)₂)_(m)CN, wherein m is 1, 2, or 3; R″ is H, halo, (C₁-C₆) alkyl,(C₁-C₆) haloalkyl, (C₃-C₉)cycloalkyl, (C₃-C₉)cycloalkyl(C₁-C₆)alkyl,(C₆-C₁₀)aryl, or (C₆-C₁₀)aryl(C₁-C₆) alkyl, or two R″ together with anatom to which they are bonded form a 3- to 9-membered ring; Z is a groupof formula

wherein a wavy line indicates a point of bonding, each of Z¹-Z⁵ isindependently N or is C substituted with an independently selected H orR⁴; provided that no more than two of Z¹-Z⁵ are N; Y is (C₁-C₂)alkyl, orsulfur; when Y is (C₁-C₂)alkyl, R⁵ and R⁶ are independently H or(C₁-C₄)alkyl or independently each R⁵ and R⁶ together with the carbonatom to which they are bonded form a carbonyl, or, one R⁵ group canfurther be bonded to X⁵ to form a 4- to 8-membered ring; and, when Y issulfur, R⁵ and R⁶ are both oxygen; or a pharmaceutically acceptable saltthereof; wherein the effective dose of the compound acts to inhibit boneresorption, improve bone formation, or both, in the patient.
 2. Themethod of claim 1, wherein Y¹ or Y² are each C and R¹ and R² areindependently H or methyl.
 3. The method of claim 1, wherein Y¹ is N andY² is C, or wherein Y¹ is C and Y² is N.
 4. The method of claim 1,wherein R³ is benzyl, α-phenethyl, α-phenpropyl, cycloalkyl orcycloalkylalkyl, any of which is unsubstituted or substituted.
 5. Themethod of claim 1, wherein R³ is heterocyclyl, heterocyclylalkyl,heteroaryl, or heteroarylalkyl, any of which is unsubstituted orsubstituted.
 6. The method of claim 1, wherein R³ is any one of:

wherein a wavy line indicates a point of attachment.
 7. The method ofclaim 1, wherein YR⁵R⁶ is SO₂.
 8. The method of claim 1, wherein Y isC₁-alkyl; and R⁵ and R⁶ are H, or wherein Y is C₂-alkyl, and R⁵ and R⁶are H.
 9. The method of claim 1, wherein R⁴ is —CO₂H, —(CH₂)_(m)CO₂H,—O(CH₂)_(m)CO₂H, —CN, —(CH₂)_(m)CN, —O(CH₂)_(m)CN, —C(CH₃)₂CO₂H,—C(CH₃)₂CN, —OC(CH₃)₂CO₂H, —OC(CH₃)₂CN, —CH(CH₃)CO₂H, —CH(CH₃)CN,—OCH(CH₃)CO₂H, —OCH(CH₃)CN; —CH(CH₂CH₃)CO₂H, —CH(CH₂CH₃)CN,—OCH(CH₂CH₃)CO₂H, —OCH(CH₂CH₃)CN; —CH(i-Pr)CO₂H, —CH(i-Pr)CN,—OCH(i-Pr)CO₂H, —OCH(i-Pr)CN, wherein iPr indicates isopropyl;—CH(t-Bu)CO₂H, —CH(t-Bu)CN, —OCH(t-Bu)CO₂H, —OCH(t-Bu)CN, wherein t-Buindicates t-butyl; —(CHR″)_(m)C(═O)N(R″)₂, —O(CHR″)_(m)C(═O)N(R″)₂,

wherein a wavy line indicates a point of attachment.
 10. The method ofclaim 1, wherein for the compound of formula (I), no Z group is presenton the ring comprising X¹-X⁵, providing a compound of formula (IA). 11.The method of claim 10, wherein the compound of formula (IA) is any oneof:

or a pharmaceutically acceptable salt thereof.
 12. The method of claim1, wherein for the compound of formula (I), Z is present, providing acompound of formula (IB).
 13. The method of claim 12, wherein Z¹-Z⁵ areall carbon.
 14. The method of claim 12, wherein the compound of formula(IB) is any one of:

or a pharmaceutically acceptable salt thereof.
 15. The method of claim1, wherein the progressive bone disease is osteoporosis, Paget'sDisease, multiple myeloma, or hyperparathyroidism.
 16. The method ofclaim 1, wherein administration of the compound of formula (I) acts toincrease FGF21 while increasing bone health.
 17. Use of a compound offormula (I) for treatment of a progressive bone disease, wherein thecompound of formula (I) is:

wherein: R is H, (C₁-C₆)alkyl, (C₃-C₉)cycloalkyl, or(C₃-C₉)cycloalkyl(C₁-C₆)alkyl; Y¹ or Y² are each independently C or N,provided that when Y¹ or Y² is N, R¹ or R², respectively, is absent; R¹and R² are independently H, (C₁-C₆)alkyl, (C₃-C₉)cycloalkyl, or(C₁-C₆)haloalkyl; or R¹ and R² together with the atoms to which they arebonded form a 5- to 9-membered ring, comprising 0-3 heteroatoms selectedfrom the group consisting of O, NR, and SO_(q) wherein q is 0, 1, or 2,and optionally mono- or multi-substituted with independently selected(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₆-C₁₀)aryl,(C₃-C₉)cycloalkyl, halo, oxo, (C₁-C₆)haloalkyl, nitro,cyano-(C₀-C₆)alkyl, R′O₂C—(C₀-C₆)alkyl, methylenedioxy,R′O—(C₀-C₆)alkyl, (R′)₂N—(C₀-C₆)alkyl, (R′)₂NC(═O)—(C₀-C₆)alkyl,R′C(═O)N(R′)—(C₀-C₆)alkyl, (C₁-C₆)alkyl-S(O)_(q)(C₀-C₆)alkyl, aryl,aroyl, or SO₂NR′₂; R³ is optionally mono- or multi-substituted(C₁-C₆)alkyl, (C₁-C₆)alkenyl, (C₁-C₆)alkynyl, (C₆-C₁₀)aryl,(C₆-C₁₀)aryl(C₁-C₆)alkyl, (3-9 membered)heterocyclyl, (3-9membered)heterocyclyl(C₁-C₆)alkyl, (3-9 membered)heteroaryl, or (3-9membered)heteroaryl(C₁-C₆)alkyl; wherein if present each substituent onR³ is independently selected from the group consisting of (C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₆-C₁₀)aryl, (C₃-C₉)cycloalkyl, 3-9membered mono- and bicyclic heterocyclyl, 3-9 membered mono- andbicyclic heteroaryl, halo, oxo, haloalkyl, haloalkoxy, nitro, cyano,CO₂R′, methylenedioxy, OR′, N(R′)₂, C(O)N(R′)₂, (C₁-C₆)alkyl-S(O)_(q),SO₂NR′₂, and (C₁-C₆)alkoxyl; and provided that group R³N(R)C(═O)— can bebonded to any one of the four carbon atoms of the phenyl ring not bondedto N¹ or Y¹; wherein each R′ is independently H, (C₁-C₆) alkyl,(C₃-C₉)cycloalkyl, (C₃-C₉)cycloalkyl(C₁-C₆)alkyl, (C₆-C₁₀)aryl, or(C₆-C₁₀)aryl(C₁-C₆) alkyl, or wherein two R′ bonded to an atom togetherwith the atom form a 3-9 membered ring optionally further comprising aheteroatom selected from the group consisting of O, NR′, and S(O)_(q);wherein any alkyl, alkenyl, alkynyl, aryl, arylalkyl, or cycloalkyl isoptionally mono- or independently multi-substituted with (C₁-C₆)alkyl,(C₁-C₆)haloalkyl, (C₁-C₆)alkoxy, (C₁-C₆)haloalkoxy, halo, oxo, aryl, oraroyl; each of X¹-X⁵ is independently N or CH, or is C substituted withan independently selected R⁴ or is C substituted with Z, provided thatno more than two of X¹-X⁵ are N, and provided that there is no more thanone Z group bonded to the ring comprising X¹-X⁵; each R⁴ isindependently halo, nitro, (C₁-C₆)fluoroalkyl, R′—(C₀-C₆)alkyl,R′O₂C—(C₀-C₆)alkyl, NC—(C₀-C₆)alkyl, R′O—(C₀-C₆)alkyl,(R′)₂N—(C₀-C₆)alkyl, (R′)₂NC(═O)—(C₀-C₆)alkyl,R′C(═O)N(R′)—(C₀-C₆)alkyl, C-bonded tetrazolyl,3-hydroxypyrrolidin-1-carbonyl, 2-hydroxyethylaminocarbonyl,cyclohexylaminocarbonyl,2-(N,N-dimethylaminocarbonyl)-2-hydroxyethylaminocarbonyl,N,N-dimethylaminoethylcarbonyl, N-methylaminocarbonyl,N-hydroxylaminocarbonyl, (1,3,4-oxadiazol-2(3H)-on)-yl,(1,2,4-oxadiazol-5(4H)-on)-3-yl, (C₁-C₆)alkyl-S(O)_(q)(C₀-C₆)alkyl,R'S(O)₂NHC(O), R′C(O)NHS(O)₂, an unsubstituted or substituted aryl, anunsubstituted or substituted heteroaryl, (C₁-C₆)alkyl or(C₃-C₉)cycloalkyl-(C₀-C₆)alkyl, wherein any alkyl or cycloalkyl isoptionally mono- or independently multi-substituted with R′, OR′,N(R′)₂, C-bonded tetrazolyl, (C₁-C₆)alkyl-S(O)_(q)(C₀-C₆)alkyl, anunsubstituted or substituted aryl, or an unsubstituted or substitutedheteroaryl; or R⁴ is —(C(R″)₂)_(m)CO₂R′, —(C(R″)₂)_(m)CON(R′)₂,—(C(R″)₂)_(m)CN, —O(C(R″)₂)_(m)CO₂R′, —O(C(R″)₂)_(m)CON(R′)₂, or—O(C(R″)₂)_(m)CN, wherein m is 1, 2, or 3; R″ is H, halo, (C₁-C₆) alkyl,(C₁-C₆) haloalkyl, (C₃-C₉)cycloalkyl, (C₃-C₉)cycloalkyl(C₁-C₆)alkyl,(C₆-C₁₀)aryl, or (C₆-C₁₀)aryl(C₁-C₆) alkyl, or two R″ together with anatom to which they are bonded form a 3- to 9-membered ring; Z is a groupof formula

wherein a wavy line indicates a point of bonding, each of Z¹-Z⁵ isindependently N or is C substituted with an independently selected H orR⁴; provided that no more than two of Z¹-Z⁵ are N; Y is (C₁-C₂)alkyl, orsulfur; when Y is (C₁-C₂)alkyl, R⁵ and R⁶ are independently H or(C₁-C₄)alkyl or independently each R⁵ and R⁶ together with the carbonatom to which they are bonded form a carbonyl, or, one R⁵ group canfurther be bonded to X⁵ to form a 4- to 8-membered ring; and, when Y issulfur, R⁵ and R⁶ are both oxygen; or a pharmaceutically acceptable saltthereof; wherein the effective dose of the compound acts to inhibit boneresorption, improve bone formation, or both, in the patient.
 18. The useof claim 17, wherein the progressive bone disease is osteoporosis,Paget's Disease, multiple myeloma, or hyperparathyroidism.
 19. The useof claim 17, wherein administration of the compound of formula (I) actsto increase FGF21 while increasing bone health.
 20. A compound offormula

or a pharmaceutically acceptable salt thereof.